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Item 1. Business

2022-03-28 compared with 2021-03-31 · 295 added, 391 removed, 36 unchanged (95% of the section changed)

Jaffe Laboratories, Inc.

is a medical device company developing tissue-based devices that are designed to be life sustaining or

life enhancing for patients with cardiovascular disease, and peripheral arterial and venous disease.

The Company’s products

are being developed to address large unmet medical needs by either offering treatments where none currently exist or by substantially

Medical Corporation is a med-tech company focused on improving the standard of care in the treatment of venous disease.

We are developing

tissue-based solutions that are designed to be life sustaining or life enhancing for patients with Chronic Venous Insufficiency (CVI).

CVI occurs when valves inside of the veins of the leg fail, resulting in insufficient blood being returned to the heart.

develop products to address large unmet medical needs by either offering treatments where none currently exist or by substantially

increasing the current standards of care.

Our products which we are developing include:

the VenoValve®, a porcine based

device to be surgically implanted in the deep venous system of the leg to treat a debilitating condition called chronic venous

insufficiency (“CVI”);

and the CoreoGraft®, a bovine based conduit to be used to revascularize the heart during

coronary artery bypass graft (“CABG”) surgeries.

Both of these products are currently being developed

for approval by the U.S.

Food and Drug Administration (“FDA”).

Our current senior management team has been affiliated

with more than 50 products that have received FDA approval or CE marking.

We currently lease a 14,507 sq.

manufacturing facility

in Irvine, California, where we manufacture products for our clinical trials and which has previously been FDA certified for commercial

manufacturing of devices.

of our products will be required to successfully complete significant clinical trials to demonstrate the safety and efficacy of

the product before it will be able to be approved by the FDA.

venous disease (“CVD”) is the world’s most prevalent chronic disease.

Our lead product is a porcine based device to be surgically implanted in the deep venous system

of the leg and is called the VenoValve®.

The VenoValve is currently being evaluated in the SAVVE U.S.

pivotal trial for the

purpose of obtaining approval to market and sell the device from the U.S.

Food and Drug Administration (“FDA”).

of officers and directors has been affiliated with numerous medical devices that have received FDA approval or CE marking and that have

been commercially successful.

We develop and manufacture our products in a 14,507 sq.

leased manufacturing facility in Irvine, California,

which has been ISO 13485-2016 certified for the design, development and manufacturing of tissue based implantable medical devices.

September 21, 2021, we announced that we were changing our name from Hancock Jaffe Laboratories, Inc.

to enVVeno Medical Corporation

and that our development strategy is to focus on the treatment of deep venous CVI.

In addition to the VenoValve, we announced

that we have a second product in the early stages of development called enVVe.

In connection with this change in strategy, we indicated

that we are not pursuing further development of the CoreoGraft, which is now outside of our primary focus area.

VenoValve is a porcine based valve developed at enVVeno Medical to be implanted in the deep venous system of the leg to treat severe

By reducing reflux, and lowering pressure (venous hypertension) within the deep venous system of the leg, the VenoValve has the

potential to reduce or eliminate the symptoms of severe deep venous CVI, including the potential to heal recurring venous leg ulcers.

The current version of the VenoValve is designed to be implanted into the femoral vein of the patient in an open surgical procedure via

a 5-to-6-inch incision in the upper thigh.

are presently no FDA approved medical devices to address valvular incompetence in the deep venous system, or effective treatments for

deep venous CVI.

Current treatment options include compression garments, or constant leg elevation, and would care for venous ulcers.

These treatments are generally ineffective, as they attempt to alleviate the symptoms of CVI without addressing the underlying causes

of the disease.

In addition, we believe compliance with compression garments and leg elevation is extremely low, especially among the

The premise behind the VenoValve is that by reducing the underlying causes of CVI, reflux and venous hypertension, the debilitating

symptoms of CVI will decrease, resulting in improvement in the quality of the lives of CVI sufferers.

estimate that there are approximately 2.4 million people in the U.S.

that suffer from deep venous CVI due to valvular incompetence.

venous disease (“CVD”) is the world’s most prevalent chronic disease.

CVD is generally classified using a standardized

2 unchanged sentences

(C0 to C6) with C5 to C6 being the most severe cases of CVD.

Venous Insufficiency (“CVI”) is a subset of CVD and is generally used to describe patients with C4 to C6 CVD.

is a condition that affects the venous system of the leg causing pain, swelling, edema, skin changes, and ulcerations.

for blood to return to the heart from the foot, ankle, and lower leg, the calf muscle pushes the blood up the veins of the leg

and through a series of one-way valves.

Each valve is supposed to open as blood passes through, and then close as blood moves

up the leg to the next valve.

CVI occurs when the one-way valves in the veins of the leg fail and become incompetent.

valves fail, blood flows backwards and in the wrong direction (reflux).

As blood pools in the lower leg, pressure inside the veins

increases (venous hypertension).

Reflux, and the resulting venous hypertension, causes the leg to swell, resulting in debilitating

pain, and in the most severe cases, venous ulcers.

The VenoValve is being developed to treat CVI in the deep venous system with

a focus on severe patients with C4b, C5 and C6 CVI.

indicate that approximately 2.4 million people in the U.S.

have C5 to C6 CVI in the deep venous system, including patients that

develop venous leg ulcers (C6 patients).

Venous Insufficiency (“CVI”) is a subset of CVD and is generally used to describe patients with C4 to C6 CVD.

CVI is a debilitating

condition that affects the venous system of the leg causing pain, swelling, edema, skin changes, and ulcerations.

The human leg contains

three vein systems:

the deep vein system, the superficial vein system, and the perforator vein system which connects the deep system

to the superficial system.

The deep venous system is located below the muscle and facia in the center portion of the leg and is responsible

for approximately 90% of the blood flow.

In order for blood to return to the heart from the foot, ankle, and lower leg, the calf muscle

serves as a pump and pushes the blood up the veins of the leg against gravity and through a series of one-way valves.

Each valve is supposed

to open as blood passes through, and then close as blood progresses up the veins of the leg to the next valve.

CVI occurs when the one-way

valves in the veins of the leg fail and become incompetent.

When the valves fail, gravity causes the blood to flow backwards and in the

wrong direction (reflux).

As blood pools in the lower leg, pressure inside the veins increases (venous hypertension).

Reflux, and the

resulting venous hypertension, causes the leg to swell, resulting in debilitating pain, and in the most severe cases, venous ulcers.

The VenoValve is being developed to treat CVI in the deep venous system with a focus on severe patients with C4b, C5 and C6 CVI.

estimate that approximately 2.4 million people in the U.S.

have C5 to C6 CVI due to reflux in the deep venous system, including patients

that develop venous leg ulcers (C6 patients).

Over one million new severe cases of CVI occur each year in the U.S., mostly from patients

who have experienced a deep vein thrombosis (blood clot).

who have experienced a deep vein thrombosis or blood clot.

The average patient seeking treatment of a venous ulcer spends as much

as $30,000 a year on wound care, and the total direct medical costs from venous ulcer sufferers in the U.S.

has been estimated

to exceed $38 billion a year.

Aside from the direct medical costs, severe CVI sufferers experience a significantly reduced quality

Daily activities such as preparing meals, housework, and personal hygiene (washing and bathing) become difficult due

to reduced mobility.

For many severe CVI sufferers, intense pain, which frequently occurs at night, prevents patients from getting

adequate sleep.

Severe CVI sufferers are known to miss approximately 40% more work days than the average worker.

A high percentage

of venous ulcer patients also experience severe itching, leg swelling, and an odorous discharge.

Wound dressing changes, which

occur several times a week, can be extremely painful.

Venous ulcers from deep venous CVI are very difficult to heal, and a significant

percentage of venous ulcers remain unhealed for more than a year.

Even if healed, recurrence rates for venous ulcers are known

to be high (20% to 40%) within the first year and as high as 60% after five years.

VenoValve is a porcine based valve developed at HJLI to be implanted in the deep venous system of the leg to treat severe CVI.

By reducing reflux, and lowering venous hypertension, the VenoValve has the potential to reduce or eliminate the symptoms of deep

venous, severe CVI, including venous leg ulcers.

The current version of the VenoValve is designed to be surgically implanted into

the patient via a 5 to 6 inch incision in the upper thigh.

are presently no FDA approved medical devices to address valvular incompetence, or effective treatments for deep venous CVI.

treatment options include compression garments, or constant leg elevation.

These treatments are generally ineffective, as they

attempt to alleviate the symptoms of CVI without addressing the underlying causes of the disease.

In addition, we believe that

compliance with compression garments and leg elevation is extremely low, especially among the elderly.

Valve transplants from

other parts of the body have been attempted, but with very-poor results.

Many attempts to create substitute valves have also failed,

usually resulting in early thromboses.

The premise behind the VenoValve is that by reducing the underlying causes of CVI, reflux

and venous hypertension, the debilitating symptoms of CVI will decrease, resulting in improvement in the quality of the lives

of CVI sufferers.

are approximately 2.4 million people in the U.S.

that suffer from deep venous CVI due to valvular incompetence.

has been estimated to exceed

$38 billion a year.

Aside from the direct medical costs, severe CVI sufferers experience a significantly reduced quality of life.

activities such as preparing meals, housework, and personal hygiene (washing and bathing) become difficult due to reduced mobility.

many severe CVI sufferers, intense pain, which frequently occurs at night, prevents patients from getting adequate sleep.

sufferers are known to miss approximately 40% more work days than the average worker.

A high percentage of venous ulcer patients also

experience severe itching, leg swelling, and an odorous discharge.

Wound dressing changes, which occur several times a week, can be extremely

Venous ulcers from deep venous CVI are very difficult to heal, and a significant percentage of venous ulcers remain unhealed

for more than a year.

Even if healed, recurrence rates for venous ulcers are known to be high (20% to 40%) within the first year and

as high as 60% after five years.

Clinical Status

consultation with the FDA, and as a precursor to the U.S.

pivotal trial, we conducted a small first-in-human study for

the VenoValve in Colombia.

The first-in-human Colombian trial included 11 patients.

In addition to providing safety and efficacy

data, the purpose of the first-in-human study was to provide proof of concept, and to provide valuable feedback to make

any necessary product modifications or adjustments to our surgical implantation procedures for the VenoValve prior to conducting

pivotal trial, we conducted a small first-in-human study for the VenoValve

in Colombia which included eleven (11) patients.

In addition to providing safety and efficacy data, the purpose of the first-in-human

study was to provide proof of concept, and to provide valuable feedback to make any necessary product modifications or adjustments to

our surgical implantation procedure for the VenoValve prior to conducting the U.S.

pivotal trial.

In December of 2018, we received regulatory approval from Instituto Nacional de Vigilancia de Medicamentos

y Alimentos (“INVIMA”), the Colombian equivalent of the FDA.

On February 19, 2019, we announced that the first VenoValve

was successfully implanted in a patient in Colombia.

Between April of 2019 and December of 2019, we successfully implanted VenoValves

in 10 additional patients, completing the implantations Colombian first-in-man study.

Overall, VenoValves have been implanted

in all 11 patients.

Endpoints for the VenoValve first-in-human study include safety (device related adverse events), reflux, measured

by doppler, a VCSS score used by the clinician to measure disease severity, and a VAS score used by the patient to measure pain.

11 patients have now completed the one-year first-in-human trial and final results from the study were released in December

Among the 11 patients, reflux improved an average of 54%, Venous Clinical Severity Scores (“VCSSs”) improved

an average of 56%, and visual analog scale (VAS) scores, which are used by patients to measure pain, have improved an average

of 76%, when compared to pre-surgery levels.

VCSS scores are commonly used by clinicians in practice and in clinical

trials to objectively assess outcomes in the treatment of venous disease, and include ten characteristics including pain,

inflammation, skin changes such as pigmentation and induration, the number of active ulcers, and ulcer duration.

The improvement

in VCSS scores is significant and indicates that almost all of the VenoValve patients who had severe CVI pre-surgery, had

mild CVI or the complete absence of disease at one-year post surgery.

safety incidences were minor with no reported device related adverse events.

Minor non-device related adverse safety

issues included one (1) fluid pocket (which was aspirated), intolerance from Coumadin anticoagulation therapy, three (3)

minor wound infections (treated with antibiotics), and one occlusion due to patient non-compliance with anti-coagulation therapy.

Endpoints for the VenoValve first-in-human

study included safety (device related adverse events), reflux, measured by doppler, a VCSS score used by the clinician to measure disease

severity and progress, a VAS score used by the patient to measure pain, and a quality of life measurement.

results from the one (1) year first-in-human study were presented at the Charing Cross International Symposium in April of 2021.

the eleven (11) patients in the study, reflux improved an average of 54%, Venous Clinical Severity Scores (“VCSSs”) improved

an average of 56%, and visual analog scale (VAS) scores, which are used by patients to measure pain, improved an average of 76%, all

at one (1) year when compared to pre-surgery levels.

VCSS scores are commonly used by clinicians in practice and in clinical trials to

objectively assess outcomes in the treatment of venous disease, and include ten characteristics including pain, inflammation, skin changes

such as pigmentation and induration, the number of active ulcers, and ulcer duration.

The improvement in VCSS scores is significant and

indicates the VenoValve patients who had severe CVI pre-surgery, had mild CVI or the complete absence of disease at one-year post surgery.

were no device related safety incidences during the one (1) year first-in-human study.

Non-device related safety incidences were minor

and included one (1) fluid pocket (which was aspirated), intolerance from Coumadin anticoagulation therapy, three (3) minor wound infections

(treated with antibiotics), and one occlusion due to patient non-compliance with anti-coagulation therapy.

preparation for the VenoValve U.S.

pivotal trial, we submitted a Pre-IDE filing with the FDA in October of 2020 and had a pre

IDE meeting with the FDA on January 11, 2021.

Topics presented at the meeting included the background and clinical need

for the VenoValve, proposed U.S.

pivotal study design, patient monitoring protocols for safety and efficacy, bench testing protocols

used to develop the device, and the VenoValve first-in-human results.

We received valuable feedback from the FDA in several areas

during the Pre-IDE meeting and believe we reached consensus on many important issues.

investigational device exemption or IDE from the FDA is required before a medical device company can proceed

with a pivotal trial for a class III medical device.

On March 5, 2021 we filed an

IDE application with the FDA for the VenoValve U.S.

pivotal trial.

Based in-part upon feedback received from the FDA during

the Pre-IDE meeting, we proposed a prospective, non-blinded, single arm, multi-center study of seventy-five (75) CVI patients

enrolled at up to 20 U.S.

Proposed endpoints for the pivotal trial mirror those endpoints used for the first-in-human trial,

and include the absence of material adverse safety events (mortality, deep wound infection, major bleeding, ipsilateral deep vein

thrombosis, pulmonary embolism) at thirty (30) days post implantation, reductions of reflux at one hundred and eighty days (180)

days post VenoValve implantation, VCSS scoring to measure disease manifestations, VAS scores to measure pain, and quality of life

measurements.

We have significant interest from key opinion leaders and several of the top vascular clinicians in the U.S.

who would like to participate in the VenoValve U.S.

pivotal trial and are in the process of qualifying potential sites for the

disease is the leading cause of death among men and women in the U.S.

accounting for about 1 in every 4 deaths.

Coronary heart

disease is the most common type of heart disease, killing over 370,000 people each year.

Coronary heart disease occurs when arteries

around the heart become blocked or occluded, in most cases by plaque.

Although balloon angioplasty with or without cardiac stents

have become the norm if one or two arteries are blocked, coronary artery bypass surgery remains the treatment of choice for patients

with multiple blocked arteries on both sides of the heart.

Approximately 200,000 coronary artery bypass graft (“CABG”)

surgeries take place each year in the U.S.

and are the most commonly performed cardiac procedure.

CABG surgeries alone account

for 55% of all cardiac surgeries, and CABG surgeries when combined with valve replacement surgeries account for approximately

62% of all cardiac surgeries.

The next largest category accounts for 10% of cardiac surgeries.

The number of CABG surgeries are

expected to increase as the population continues to age.

On average, three grafts are used for each CABG surgery.

CABG surgeries are invasive, improved surgical techniques over the years have lowered the fatality rate from CABG surgeries to

between 1% and 3% prior to discharge from the hospital.

Arteries around heart are accessed via an incision along the sternum known

as a sternotomy.

Once the incision is made, the sternum (chest) is divided (“cracked”) to access the heart and its

surrounding arteries.

surgery is relatively safe and effective.

In most instances, doctors prefer to use the left internal mammary artery (“LIMA”),

an artery running inside the ribcage and close to the sternum, to re-vascularize the left side of the heart.

Use of the LIMA to

revascularize the left descending coronary artery (known as the “widow maker”) has become the gold standard for revascularizing

the left side of the heart during CABG surgeries.

For the right side of the heart, and where additional grafts are needed on the

left side, the current standard of care is to harvest the saphenous vein from the patient’s leg to be dissected into pieces

and used as bypass grafts around the heart.

Unfortunately, saphenous vein grafts (“SVGs”) are not nearly as effective

as the LIMA for revascularizing the heart.

In fact, SVGs continue to be the weak link for CABG surgeries.

saphenous vein harvest procedure is itself invasive.

Either a long incision is made along the inner leg of the patient to harvest

the vein, or the saphenous vein is extracted endoscopically.

Regardless of the type of harvest procedure, bypass graft harvest

remains an invasive and complication prone aspect of the CABG procedure.

Present standard-of-care complications are described

in recent published reports in major medical journals.

The percentage of complications from the harvest procedure can be as high

This is mainly due to non-healing of the saphenous wound or development of infection in the area of the saphenous vein

harvest site.

the LIMA is known for excellent short term and long term patency rates, studies indicate that between 10% and 40% percent of SVGs

that are used as conduits for CABG surgeries fail within the first year after the CABG surgery.

A significant percentage fail

within the first 30 days.

At 10 years, the SVGs failure rate can be as high as 75%.

When a graft fails, it becomes blocked or

occluded, depriving the heart of blood flow.

Mortality during the first year after bypass graft failure is very high, between

For purposes of comparison, a 3% threshold is considered to be a high cardiac risk.

In fact, a relatively recent study

in Denmark has reported that mortality rates at 8 to 10 years after CABG surgery are as high as 60% to 80%.

While a life expectancy

of 8 to 10 years following CABG surgery may have been acceptable in the past, expectations have changed and with people now generally

living longer, additional focus is now being placed on extending life expectancies following CABG surgeries.

have determined that there are two main causes of SVGs failure:

size mismatch, and a thickening of the interior of the SVGs that

begins immediately following the harvest procedure.

Size mismatch occurs because the diameter of SVGs is often significantly larger

than the diameter of the coronary arteries around the heart.

This size mismatch causes flow disturbances, leading to graft thromboses

and graft failure.

The thickening of the cell walls of SVGs occur when a layer of endothelial cells on the inner surface of the

SVGs are disturbed beginning at the harvesting procedure, starting a chain reaction which causes the cells to thicken and the

inside of the graft to narrow, resulting in blood clots and graft failure.

CoreoGraft is a bovine based off the shelf conduit that could potentially be used to revascularize the heart, instead of harvesting

the saphenous vein from the patient’s leg.

In addition to avoiding the invasive and painful SVG harvest process, HJLI’s

CoreoGraft closely matches the size of the coronary arteries, eliminating graft failures that occur due to size mismatch.

with no graft harvest needed, the CoreoGraft could also reduce or eliminate the inner thickening that burdens and leads to failure

addition to providing a potential alternative to SVGs, the CoreoGraft could be used when making grafts from the patients’

own arteries and veins is not an option.

For example, patients with significant arterial and vascular disease often do not have

suitable vessels to be used as grafts.

For other patients, such as women who have undergone radiation treatment for breast cancer

and have a higher incidence of heart disease, using the LIMA may not be an option if it was damaged by the radiation.

example are patients undergoing a second CABG surgery.

Due in large part to early SVG failures, patients may need a second CABG

If the SVG was used for the first CABG surgery, the patient may have insufficient veins to harvest.

While the CoreoGraft

may start out as a product for patients with no other options, if the CoreoGraft establishes good short term and long term patency

rates, it could become the graft of choice for all CABG patients in addition to the LIMA.

January of 2020, we announced the results of a six-month, nine sheep, animal feasibility study for the CoreoGraft.

Bypasses were

accomplished by attaching the CoreoGrafts from the ascending aorta to the left anterior descending artery, and surgeries were

preformed both on-pump and off-pump.

Partners for the feasibility study included the Texas Heart Institute, and American Preclinical

subjects were evaluated via angiograms and flow monitors during the study, and a full pathology examination of the CoreoGrafts

and the surrounding tissue was performed post necropsy.

results from the feasibility study demonstrated that the CoreoGrafts remained patent (open) and fully functional at 30, 90, and

180 day intervals after implantation.

In addition, pathology examinations of the grafts and surrounding tissue at the conclusion

of the study showed no signs of thrombosis, infection, aneurysmal degeneration, changes in the lumen, or other problems that are

known to plague and lead to failure of SVGs.

addition to exceptional patency, pathology examinations indicated full endothelialization for grafts implanted for 180 days both

throughout the CoreoGrafts and into the left anterior descending arteries.

Endothelium is a layer of cells that naturally exist

throughout healthy veins and arteries and that act as a barrier between blood and the surrounding tissue, which helps promote

the smooth passage of blood.

Endothelium are known to produce a variety anti-clotting and other positive characteristics that

are essential to healthy veins and arteries.

The presence of full endothelialization within the longer term CoreoGrafts indicates

that the graft is being accepted and assimilated in a manner similar to natural healthy veins and arteries that exist throughout

the vascular system and is an indication of long-term biocompatibility.

May of 2020, we announced that we had received approval from the Superintendent of Health of the National Health Counsel for the

Republic of Paraguay to conduct a first-in-human trial for the CoreoGraft.

Up to 5 patients that need coronary artery bypass graft

surgery will receive CoreoGraft implants as part of the first-in-human study.

In July of 2020, we announced that we had received

permission to proceed with the first-in-human study, which had been put on hold due to the COVID-19 pandemic, and in August of

2020 we announced that the first two patients had been enrolled for the first-in-human CoreoGraft trial.

Heart bypass surgeries

for the first two patients to receive CoreoGraft implants as part of our first-in-human trial were successfully completed in October

A third bypass surgery using the CoreoGraft was successfully completed in November of 2020.

Two CoreoGraft surgical patients

have expired due to what we believe are non-device related adverse events, one in October and one in November of 2020.

Pursuant to our protocol for the first-in-human trial, these events are being reviewed by a data and safety monitoring board

and pending the outcome of the review, we expect to resume enrolling patients for the study in the second quarter of 2021.

product candidates and our operations are subject to extensive regulation by the FDA, and other federal and state authorities

in the United States, as well as comparable authorities in foreign jurisdictions.

Our product candidates are subject to regulation

as medical devices in the United States under the Federal Food, Drug, and Cosmetic Act (“FDCA”), as implemented and

enforced by the FDA.

The FDA regulates the development, design, non-clinical and clinical research, manufacturing, safety, efficacy,

labeling, packaging, storage, installation, distribution, servicing, recordkeeping, premarket clearance or approval, adverse event

reporting, advertising, promotion, marketing, and import and export of medical devices to ensure that medical devices distributed

domestically are safe and effective for their intended uses and otherwise meet the requirements of the FDCA.

pivotal trial, on March 5, 2021, we submitted an IDE application with the FDA.

investigational device exemption or IDE from the FDA is required before a medical device company can proceed with a pivotal trial for

a class III medical device.

On April 1, 2021, we received notification from the FDA that our IDE application was approved.

We have named

pivotal trial for the VenoValve the SAVVE (Surgical Anti-reflux Veno Valve Endoprosthesis) study.

It is a prospective,

non-blinded, single arm, multi-center study of seventy-five (75) CVI patients to be enrolled at up to 20 U.S.

modifications for the VenoValve were necessary following the first-in-human study and the SAVVE trial is evaluating the same device that

was used in the first-in-human study.

Endpoints for the SAVVE trial mirror those endpoints used for the first-in-human study.

The primary safety endpoint for the pivotal trial is a material adverse safety event (mortality, deep wound infection, major bleeding,

ipsilateral deep vein thrombosis, pulmonary embolism) in no more than twenty six percent (26%) of the patients at one (1) month

post implantation, and the primary effectiveness endpoint for the pivotal trial is improvement in reflux of at least thirty percent (30%),

measured at six (6) months post VenoValve implantation.

In the first-in-human study there were no reported material adverse safety events

at one (1) month post implantation, and reflux improved an average of fifty six percent (56%) at six (6) months post implantation.

scoring to measure disease manifestations, VAS scores to measure pain, and quality of life measurements will also be monitored in the

August 3, 2020, we announced that the FDA granted Breakthrough Device Designation status to the VenoValve.

The FDA’s Breakthrough

Devices Program was established to enable priority review for devices that provide more effective treatment or diagnosis of life threatening

or irreversibly debilitating diseases or conditions.

The goal of the FDA’s Breakthrough Devices Program is to provide patients

and health care providers with timely access to medical devices by speeding up their development, assessment, and review, while preserving

the FDA’s mission to protect and promote public health.

the end of the VenoValve first-in-human study, eight (8) study participants agreed to additional monitoring.

In August of 2021, longer

term follow-up data was presented at the Society of Vascular Surgery Conference in San Diego, for the cohort of eight (8) patients.

data indicated no recurrences of the severe CVI that was present pre-VenoValve, including no ulcer recurrences for those patients whose

venous ulcers had healed following VenoValve surgery.

There were no reported safety issues from the end of one (1) year first-in-human

study to the end of the two (2) year reporting period.

In addition, the patients continued to improve, reporting 63%, 60%, and 93%, average

improvements in reflux, VCSS, and VAS scores, respectively, at an average of two (2) years post VenoValve surgery compared to pre-VenoValve

October of 2021, we announced that the first patient in the SAVVE pivotal trial underwent successful VenoValve implantation surgery

and had been discharged from the hospital.

The surgery was performed by Dr.

Adriana Laser, associate professor of surgery at Albany

Medical College and a vascular surgeon with Albany Med Vascular Surgery.

As of December 31, 2021, ten (10) of our clinical trial

sites were activated and eligible to enroll patients in the SAVVE pivotal trial.

As of March 24, 2022 we have sixteen (16)

clinical trial sites that are active to enroll patients in the SAVVE trial and expect to have nineteen (19) active sites by March

Also, as of March 24, 2022, we have completed nine (9) successful surgeries in the SAVVE pivotal trial for the VenoValve.

We expect to have our tenth surgery completed by March 31, 2022.

resurgence of COVID and the Omicron variant had both direct and indirect consequences on our clinical trial.

Several of our clinical

sites put elective surgeries on hold and prohibited potential study subjects from coming to the hospital for screening.

Further, as reported

in the media, COVID resurgences put an enormous strain on all hospital resources including clinical staffs.

In addition to caring for

the influx of COVID patients, hospitals become short staffed due to their own employees’ COVID sicknesses, resulting in clinical

staff being reassigned to cover the shortfall.

The lack of available clinical personnel both slows enrollment and impacts the speed at

which we can activate clinical sites.

COVID impacts our patient population.

Patients with COVID or who have had COVID within ninety (90) days of their screening, are excluded

from our study until after the ninety (90) day period has passed.

In addition, concerns about getting COVID impact the patients’

willingness to undergo an elective surgical procedure with a one-night hospital stay.

As hospital clinical operations return to more

normal levels, our goal is to fully enroll the SAVVE pivotal trial by the end of 2022 or the beginning of 2023.

continue to monitor the ongoing overall impact of COVID on the SAVVE clinical trial and will issue updates when appropriate.

February of 2021, we raised $41.4 million of capital in a public offering of our common stock.

In September of 2021, we raised

$20 million dollars of capital in a registered direct offering priced at the market under Nasdaq rules and purchased by a fund

managed by Perceptive Advisors, a leading life sciences investment firm.

We finished 2021 with approximately $55 million of cash.

At our existing cash burn rate of approximately $4 million per quarter, we should have sufficient cash to fund operations through the

end of 2024 and into 2025.

With primary endpoints following full enrollment in the SAVVE pivotal trial of thirty (30) days for safety,

and six (6) months for effectiveness, we expect to have primary endpoint data well in advance of the need to raise additional capital.

product candidates and our operations are subject to extensive regulation by the FDA, and other federal and state authorities in the

United States, as well as comparable authorities in foreign jurisdictions.

Our product candidates are subject to regulation as medical

devices in the United States under the Federal Food, Drug, and Cosmetic Act (“FDCA”), as implemented and enforced by the

The FDA regulates the development, design, non-clinical and clinical research, manufacturing, safety, efficacy, labeling, packaging,

storage, installation, distribution, servicing, recordkeeping, premarket clearance or approval, adverse event reporting, advertising,

promotion, marketing, and import and export of medical devices to ensure that medical devices distributed domestically are safe and effective

for their intended uses and otherwise meet the requirements of the FDCA.

Approval Pathway

III devices such as the VenoValve and the CoreoGraft generally require pre-market approval (PMA) before they can

be marketed in the U.S.

The PMA review and approval process is more demanding than the 510(k) premarket notification process.

In a PMA, the manufacturer must demonstrate that the device is safe and effective, and the PMA must be supported by extensive

data, including data from preclinical studies and human clinical trials.

The PMA also must contain a full description of the device

and its components, a full description of the methods, facilities and controls used for manufacturing, and proposed labeling.

Following receipt of a PMA, the FDA determines whether the application is sufficiently complete to permit a substantive review.

If FDA accepts the application for review, it has 180 days under the FDCA to complete its review of a PMA, although in practice,

the FDA’s review often takes significantly longer, and can take several years.

An advisory panel of experts from outside

the FDA may be convened to review and evaluate the application and provide recommendations to the FDA as to the approvability

of the device.

The FDA may or may not accept the panel’s recommendation.

In addition, the FDA generally will conduct a pre-approval

inspection of the applicant or its third-party manufacturers’

manufacturing facility or facilities to ensure compliance

with the QSR.

The FDA will approve the new device for commercial distribution if it determines that the data and information in

the PMA constitute valid scientific evidence and that there is reasonable assurance that the device is safe and effective for

its intended use(s).

FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including,

among other things, restrictions on labeling, promotion, sale and distribution, and collection of long-term follow-up data

from patients in the clinical study that supported PMA approval, or requirements to conduct additional clinical studies post-approval.

The FDA may condition PMA approval on some form of post-market surveillance when deemed necessary to protect the public health

or to provide additional safety and efficacy data for the device in a larger population or for a longer period of use.

cases, the manufacturer might be required to follow certain patient groups for a number of years and to make periodic reports

to the FDA on the clinical status of those patients.

Failure to comply with the conditions of approval can result in material

adverse enforcement action, including withdrawal of the approval.

Certain changes to an approved device, such as changes in manufacturing

facilities, methods or quality control procedures, or changes in the design performance specifications, which affect the safety

or effectiveness of the device, require submission of a PMA supplement.

PMA supplements often require submission of the same type

of information as a PMA, except that the supplement is limited to information needed to support any changes from the device covered

by the original PMA and may not require as extensive clinical data or the convening of an advisory panel.

Certain other changes

to an approved device require the submission of a new PMA, such as when the design change causes a different intended use, mode

of operation and technical basis of operation, or when the design change is so significant that a new generation of the device

will be developed, and the data that were submitted with the original PMA are not applicable for the change in demonstrating a

reasonable assurance of safety and effectiveness.

We believe that the VenoValve and the CoreoGraft each will require the approval

III devices such as the VenoValve generally require pre-market approval (PMA) before they can be marketed in the U.S.

The PMA review

and approval process is more demanding than the 510(k) premarket notification process.

In a PMA, the manufacturer must demonstrate that

the device is safe and effective, and the PMA must be supported by extensive data, including data from preclinical studies and human

clinical trials.

The PMA also must contain a full description of the device and its components, a full description of the methods, facilities

and controls used for manufacturing, and proposed labeling.

Following receipt of a PMA, the FDA determines whether the application is

sufficiently complete to permit a substantive review.

If FDA accepts the application for review, it has 180 days under the FDCA to complete

its review of a PMA, although in practice, the FDA’s review often takes significantly longer, and can take several years.

panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA as

to the approvability of the device.

The FDA may or may not accept the panel’s recommendation.

In addition, the FDA generally will

conduct a pre-approval inspection of the applicant or its third-party manufacturers’ manufacturing facility or facilities to ensure

compliance with the QSR.

The FDA will approve the new device for commercial distribution if it determines that the data and information

in the PMA constitute valid scientific evidence and that there is reasonable assurance that the device is safe and effective for its

intended use(s).

FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including, among other

things, restrictions on labeling, promotion, sale and distribution, and collection of long-term follow-up data from patients in the clinical

study that supported PMA approval, or requirements to conduct additional clinical studies post-approval.

The FDA may condition PMA approval

on some form of post-market surveillance when deemed necessary to protect the public health or to provide additional safety and efficacy

data for the device in a larger population or for a longer period of use.

In such cases, the manufacturer might be required to follow

certain patient groups for a number of years and to make periodic reports to the FDA on the clinical status of those patients.

to comply with the conditions of approval can result in material adverse enforcement action, including withdrawal of the approval.

changes to an approved device, such as changes in manufacturing facilities, methods or quality control procedures, or changes in the

design performance specifications, which affect the safety or effectiveness of the device, require submission of a PMA supplement.

supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information needed

to support any changes from the device covered by the original PMA and may not require as extensive clinical data or the convening of

an advisory panel.

Certain other changes to an approved device require the submission of a new PMA, such as when the design change causes

a different intended use, mode of operation and technical basis of operation, or when the design change is so significant that a new

generation of the device will be developed, and the data that were submitted with the original PMA are not applicable for the change

in demonstrating a reasonable assurance of safety and effectiveness.

The VenoValve will require the approval of a PMA.

Trials in Support of PMA

trials are almost always required to support a PMA submission.

All clinical investigations of devices to determine safety and

effectiveness must be conducted in accordance with the FDA’s investigational device exemption (IDE) regulations,

which govern investigational device labeling, prohibit promotion of the investigational device and specify an array of recordkeeping,

reporting and monitoring responsibilities of study sponsors and study investigators.

If the device presents a “significant

to human health, as defined by the FDA, the FDA requires the device sponsor to submit an IDE application to the FDA,

which must become effective prior to commencing human clinical trials.

A significant risk device is one that presents a potential

for serious risk to the health, safety or welfare of a patient and either is implanted, used in supporting or sustaining human

life, substantially important in diagnosing, curing, mitigating or treating disease or otherwise preventing impairment of human

health, or otherwise presents a potential for serious risk to a subject.

Both the VenoValve and the CoreoGraft will likely

require IDE applications prior to human testing in the United States.

IDE application must be supported by appropriate data, such as animal and laboratory test results, showing that it is safe to

test the device in humans and that the testing protocol is scientifically sound.

The IDE will automatically become effective 30

days after receipt by the FDA unless the FDA notifies the company that the investigation may not begin.

If the FDA determines

that there are deficiencies or other concerns with an IDE for which it requires modification, the FDA may permit a clinical trial

to proceed under a conditional approval.

addition to IDE approval, a human, the study must be approved by, and conducted under the oversight of, an Institutional

Review Board, or IRB, for each clinical site.

The IRB is responsible for the initial and continuing review of the study,

and may pose additional requirements for the conduct of the study.

If an IDE application is approved by the FDA and one or more

IRBs, human clinical trials may begin at a specific number of investigational sites with a specific number of patients, as approved

Acceptance of an IDE application for review does not guarantee that the FDA will allow the IDE to become effective

and, if it does become effective, the FDA may or may not determine that the data derived from the trials support the safety and

effectiveness of the device or warrant the continuation of clinical trials.

An IDE supplement must be submitted to, and approved

by, the FDA before a sponsor or investigator may make a change to the investigational plan that may affect its scientific soundness,

study plan or the rights, safety or welfare of human subjects.

During a study, the sponsor is required to comply with the applicable

FDA requirements, including, for example, trial monitoring, selecting clinical investigators and providing them with the investigational

plan, ensuring IRB review, adverse event reporting, record keeping and prohibitions on the promotion of investigational devices

or on making safety or effectiveness claims for them.

The clinical investigators in the clinical study are also subject to FDA’s

regulations and must obtain patient informed consent, rigorously follow the investigational plan and study protocol, control the

disposition of the investigational device and comply with all reporting and recordkeeping requirements.

Additionally, after a

trial begins, we, the FDA or the IRB could suspend or terminate a clinical trial at any time for various reasons, including a

belief that the risks to study subjects outweigh the anticipated benefits.

All clinical investigations of devices to determine safety and effectiveness

must be conducted in accordance with the FDA’s investigational device exemption (IDE) regulations, which govern investigational

device labeling, prohibit promotion of the investigational device and specify an array of recordkeeping, reporting and monitoring responsibilities

of study sponsors and study investigators.

If the device presents a “significant risk,” to human health, as defined by the

FDA, the FDA requires the device sponsor to submit an IDE application to the FDA, which must become effective prior to commencing human

clinical trials.

A significant risk device is one that presents a potential for serious risk to the health, safety or welfare of a patient

and either is implanted, used in supporting or sustaining human life, substantially important in diagnosing, curing, mitigating or treating

disease or otherwise preventing impairment of human health, or otherwise presents a potential for serious risk to a subject.

VenoValve required IDE applications prior to human testing in the United States, and we believe any future products such as

the enVVE will also require IDE applications before human testing in the United States.

IDE application must be supported by appropriate data, such as animal and laboratory test results, showing that it is safe to test the

device in humans and that the testing protocol is scientifically sound.

The IDE will automatically become effective 30 days after receipt

by the FDA unless the FDA notifies the company that the investigation may not begin.

If the FDA determines that there are deficiencies

or other concerns with an IDE for which it requires modification, the FDA may permit a clinical trial to proceed under a conditional

addition to IDE approval, a human, the study must be approved by, and conducted under the oversight of, an Institutional Review Board,

or IRB, for each clinical site.

The IRB is responsible for the initial and continuing review of the study, and may pose additional requirements

for the conduct of the study.

If an IDE application is approved by the FDA and one or more IRBs, human clinical trials may begin at a

specific number of investigational sites with a specific number of patients, as approved by the FDA.

Acceptance of an IDE application

for review does not guarantee that the FDA will allow the IDE to become effective and, if it does become effective, the FDA may or may

not determine that the data derived from the trials support the safety and effectiveness of the device or warrant the continuation of

clinical trials.

An IDE supplement must be submitted to, and approved by, the FDA before a sponsor or investigator may make a

change to the investigational plan that may affect its scientific soundness, study plan or the rights, safety or welfare of human subjects.

During a study, the sponsor is required to comply with the applicable FDA requirements, including, for example, trial monitoring, selecting

clinical investigators and providing them with the investigational plan, ensuring IRB review, adverse event reporting, record keeping

and prohibitions on the promotion of investigational devices or on making safety or effectiveness claims for them.

The clinical investigators

in the clinical study are also subject to FDA’s regulations and must obtain patient informed consent, rigorously follow the investigational

plan and study protocol, control the disposition of the investigational device and comply with all reporting and recordkeeping requirements.

Additionally, after a trial begins, we, the FDA or the IRB could suspend or terminate a clinical trial at any time for various reasons,

including a belief that the risks to study subjects outweigh the anticipated benefits.

a device is cleared or approved for marketing, numerous and pervasive regulatory requirements continue to apply.

These include:

establishing registration and device listing with the FDA;

QSR requirements, which require manufacturers, including third-party

manufacturers, to follow stringent design, testing, control, documentation and other quality assurance procedures during all aspects

of the design and manufacturing process;

labeling regulations and FDA prohibitions against the promotion of investigational products,

or “off-label”

registration and device listing with the FDA;

QSR requirements, which require manufacturers, including third-party manufacturers, to

follow stringent design, testing, control, documentation and other quality assurance procedures during all aspects of the design and

manufacturing process;

labeling regulations and FDA prohibitions against the promotion of investigational products, or “off-label”

uses of cleared or approved products;

requirements related to promotional activities;

approval of product modifications that could significantly affect safety or effectiveness or that would constitute a major change

in intended use of one of our cleared devices;

medical device reporting regulations, which require that a manufacturer report

to the FDA if a device it markets may have caused or contributed to a death or serious injury, or has malfunctioned and the device

or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were

correction, removal and recall reporting regulations, which require that manufacturers report to the FDA field corrections

and product recalls or removals if undertaken to reduce a risk to health posed by the device or to remedy a violation of the FDCA;

clearance or approval of product modifications

that could significantly affect safety or effectiveness or that would constitute a major change in intended use of one of our cleared

medical device reporting regulations, which require that a manufacturer report to the FDA if a device it markets may have caused

or contributed to a death or serious injury, or has malfunctioned and the device or a similar device that it markets would be likely

to cause or contribute to a death or serious injury, if the malfunction were to recur;

correction, removal and recall reporting regulations,

which require that manufacturers report to the FDA field corrections and product recalls or removals if undertaken to reduce a risk to

health posed by the device or to remedy a violation of the FDCA;

and post-market surveillance activities and regulations.

1 unchanged sentence

country or territory outside of the U.S.

has its own rules and regulations with respect to the manufacture, marketing and sale

of medical devices.

For example, in December of 2018, we received regulatory approval from Instituto Nacional de Vigilancia de

Medicamentos y Alimentos (“INVIMA”), the Colombian equivalent of the U.S.

Food and Drug Administration, for our first-in-human

trial for the VenoValve in Colombia.

At this time, other than the first-in-human trial in Colombia, we have not determined which

countries outside of the U.S., if any, for which we will seek approval for our product candidates.

has its own rules and regulations with respect to the manufacture, marketing and sale of medical

For example, in December of 2018, we received regulatory approval from Instituto Nacional de Vigilancia de Medicamentos y Alimentos,

the Colombian equivalent of the U.S.

Food and Drug Administration, for our first-in-human study for the VenoValve in Colombia.

At this time, other than the first-in-human trial in Colombia, we have not determined which countries outside of the U.S., if any, we

will seek approval for our product candidates.

Competitive Strengths

believe we will offer the cardiovascular device market a compelling value proposition with the launch of our two product candidates,

believe we will offer the venous disease treatment market a compelling value proposition with the launch of our product candidates,

if approved, for the following reasons:

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Our facility is designed expressly for the manufacture

of Class III tissue based implantable medical devices and is equipped for research and development, prototype fabrication,

current good manufacturing practices, or cGMP, and manufacturing and shipping for Class III medical devices, including biologic

cardiovascular devices.

have attracted senior executives who are experienced in research and development and who have worked on over 50 medical devices

of Class III tissue based implantable medical devices and is equipped for research and development, prototype fabrication, current

good manufacturing practices, or cGMP, and manufacturing and shipping for Class III medical devices, including biologic cardiovascular

have attracted senior executives who are experienced in research and development and who have worked on numerous medical devices

that have received FDA approval or CE marking.

We also have the advantage of an experienced board of directors and scientific

advisory board who will provide guidance as we move towards market launch.

We also have the advantage of an experienced board of directors and scientific advisory

board who will provide guidance as we move towards market launch.

possess an extensive proprietary processing and manufacturing methodology specifically applicable to the design, processing, manufacturing

and sterilization of biologic devices.

This includes FDA compliant quality control and assurance programs, proprietary tissue

processing technologies demonstrated to eliminate recipient immune responses, trusted relationship with abattoir suppliers, and

a combination of tissue preservation and gamma irradiation that enhances device functions and guarantees sterility.

We have filed

several patent applications for the VenoValve and CoreoGraft with the U.S.

Patent and Trademark Office (USPTO)

and throughout the world.

In February of 2021, we received a notice for allowance from the USPTO for an application

focusing on novel aspects of the VenoValve Frame.

This includes FDA compliant quality control and assurance programs, proprietary tissue processing

technologies demonstrated to eliminate recipient immune responses, trusted relationship with abattoir suppliers, and a combination of

tissue preservation and gamma irradiation that enhances device functions and guarantees sterility.

We have filed several patent applications

for the VenoValve with the U.S.

Patent and Trademark Office (USPTO) and throughout the world.

In February of 2021, we

received a notice for allowance from the USPTO for an application focusing on novel aspects of the VenoValve Frame.

of March 24, 2022, we had 24 full-time employees.

None of our employees are represented by a collective bargaining

agreement, and we have never experienced any work stoppage.

None of our employees are represented by a collective bargaining agreement,

and we have never experienced any work stoppage.

We believe we have good relations with our employees.

2 unchanged sentences

and our telephone number is (949) 261-2900.

Our corporate website address is www.hancockjaffe.com.

The information contained

on or accessible through our website is not a part of this prospectus, and the inclusion of our website address in this prospectus

is an inactive textual reference only.

Our corporate website address is www.envveno.com.

The information contained on or accessible

through our website is not a part of this prospectus, and the inclusion of our website address in this prospectus is an inactive textual

reference only.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business