DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant claims herein are examined utilizing the accepted effective filing date of 01/28/2019 for the basis of any prior art rejections.
Claim Objections
Claims 2-7 are objected to because of the following informalities:
Claims 2-7 are missing a comma before the wherein clause. The examiner suggests amending the claims to include the missing comma, e.g., “The method of claim 2, wherein . . .”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13-15, 18, and 20 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 recites the limitation "the . . . progeny thereof and/or soluble factors". There is insufficient antecedent basis for this limitation in the claim as there are no previous recitations of cell progeny or soluble factors in claim 1 of which this claim depends. Thus, the claim is indefinite.
Claim 14 recites the limitation "the . . . progeny thereof and/or soluble factors". There is insufficient antecedent basis for this limitation in the claim as there are no previous recitations of cell progeny or soluble factors in claim 9 of which this claim depends. Thus, the claim is indefinite.
Claim 15 recites the limitation "the . . . progeny thereof and/or soluble factors". There is insufficient antecedent basis for this limitation in the claim as there are no previous recitations of cell progeny or soluble factors in claim 1 of which this claim depends. Thus, the claim is indefinite.
Claim 18 recites the limitation "the . . . progeny thereof ". There is insufficient antecedent basis for this limitation in the claim as there are no previous recitations of cell progeny or soluble factors in claim 1 of which this claim depends. Thus, the claim is indefinite.
Claim 20 recites the limitation "the . . . progeny thereof ". There is insufficient antecedent basis for this limitation in the claim as there are no previous recitations of cell progeny or soluble factors in claim 1 of which this claim depends. Thus, the claim is indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for method of reducing incidence of GI bleeding via direct injection of STRO-3+ bone marrow mesenchymal stem cells, does not reasonably provide enablement for preventing GI bleeding broadly in any subject in need via any other MSCs and administration routes embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Claims 1-9, 12-16, and 18-19 are directed to a method of treating gastrointestinal (GI) bleeding in a subject in need thereof, the method comprising administering to the subject a composition comprising mesenchymal lineage precursor or stem cells (MLPSCs). Claim 2 specifies the GI bleeding is caused by complications arising from left ventricular assist device (LVAD) implantation in the subject. Claim 3 specifies the GI bleeding is associated with inflammation arising from LVAD implantation in the subject. Claim 4 specifies the LVAD implantation is a bridge to transplant (BTT) or destination therapy (DT). Claim 5 specifies the subject is undergoing treatment or has been treated for heart failure. Claim 6 specifies the heart failure is due to hypertension, cardiomyopathy, myocarditis, obesity, or diabetes. Claim 7 specifies that the subject has advanced ischemic or non-ischemic heart failure. Claim 8 specifies wherein the subject has an inflamed myocardium. Claim 9 specifies the GI bleeding is associated with aortic stenosis, von Willebrand's disease or epistaxis. Claim 12 specifies the GI bleeding is associated with a disorder selected from hemorrhoids, peptic ulcers, a tear in the esophagus, or inflammation in the esophagus, diverticulosis, diverticulitis, ulcerative colitis, Crohn's disease, colonic polyps, colon cancer, stomach cancer or esophageal cancer. Claim 13 specifies that the MLPSCs are administered to the subject by a catheter-based system. Claim 14 specifies that the MLPSCs are administered to the subject by one or more of transendocardial injection, intracoronary infusion, or intravenous infusion. Claim 15 specifies that the MLPSCs are administered to the subject between about 1- and 7-days following diagnosis of heart failure. Claim 16 specifies that the composition comprises a population of culture expanded MLPSCs, wherein the culture expanded MLPSCs are culture expanded from a population of STRO-1+ MLPSCs. Claim 18 specifies wherein the population of MLPSCs are administered to the subject or the heart over multiple doses. Claim 19 specifies administering about 1.5 x 108 cells MLPSCs to the subject. Claim 24 is directed to method of treatment which comprises the steps of: i) selecting a subject showing signs of GI bleeding or at risk of developing GI bleeding, and, ii) administering to the subject a composition comprising mesenchymal lineage stem or precursor cells.
Nature of the invention:
A method of treating or preventing gastrointestinal (GI) bleeding in a subject in need thereof, the method comprising administering to the subject a composition comprising mesenchymal lineage precursor or stem cells (MLPSCs).
The state of the prior art:
The state of the prior art for preventing GI bleeding in various subjects in need (cancer patients, Covid patients, diabetics, ulcerative colitis patients, surgical patients, people with bacterial infection, etc.) via various administration routes was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass a method of treating GI bleeding in various subjects in need via various administration routes, wherein the various administration routes include direct injection, subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, topical administration etc.
The level of skill in the art:
The level of skill is high such that it requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification discloses working examples in which mesenchymal lineage precursor cells are obtained from bone marrow (paras 0150-0151) and immunoselected from bone marrow mononuclear cells for MSC expressing STRO-3 (para 0152-0155). A pilot trial using selected MLPSCs was performed in which 30 patients with LVADs were enrolled and received either MPCs or control therapy (para 0156), which resulted in increased time to first hospitalization due to major GI bleed and 75% reduction in cumulative incidence of at least one hospitalization from GI bleeding over 6 months (same para). The working examples also describe an expanded confirmatory LVAD-MPC study design and results in which MPC groups (delivered via injecting 150 M allogeneic MPCs into the native myocardium of LVAD recipients) showed significantly linger time to first hospitalization due to major GI bleeding, 48% reduction in cumulative incidence of at least one hospitalization from GI bleeding, and 76% reduction in rate of major GI bleeding events at 6 months (para 0157-0159).
The specification fails to provide any working examples in which GI bleeding is prevented generally or treated in any other patients (people with aortic stenosis, von Willebrand’s disease, epistaxis as in claim 9, those with Crohn’s or ulcerative colitis, etc.) using any other mesenchymal stem cells via any other administration routes (intravenous, topical, transdermal, etc.).
The unpredictable nature of the art:
The claims read on preventing and treating GI bleeding in any subject in need (i.e., has disease state that needs to be treated) by administering MLPSCs via various administration routes.
Subject in need and treatment:
The claims encompass preventing or treating any subject having GI bleeding. However, GI bleeding cannot be prevented. Moreover, not all GI bleeds can be treated the same way. A post-dated article from Mayo Clinic (“Gastrointestinal bleeding”, 4 Aug 2020; Accessed from the Internet 21 Aug 2026; Retrieved from https://www.mayoclinic.org/diseases-conditions/gastrointestinal-bleeding/diagnosis-treatment/drc-20372732) states that gastrointestinal bleeding can happen either in the upper or lower GI tract (“Causes”). Upper GI bleeding can be caused by peptic ulcer, tears in the esophagus, esophagitis, hiatal hernia, as well as cancerous and non-cancerous growths (“Upper GI bleeding”). Lower GI bleeding can be caused by diverticulitis, tumors, hemorrhoids, fissures, and IBD for example (“Lower GI bleeding”). It also states that GI bleeding can be treated in various manners depending on where the bleeding is from (“Treatment” para 1).
Post-dated Vedachalam et al (World J Gastroenterol. 2020 May 28;26(20):2550-2558; reference in IDS filed 10/28/2025) states that left ventricular assist devices (LVAD) are becoming common as life prolonging therapy in patients with advanced heart failure (abstract). Unfortunately, continuous flow LVADs are fraught with complications such as gastrointestinal (GI) bleeding that are primarily attributed to the formation of arteriovenous malformations (same para). Small bowel bleeds account for 15% as the source and patients often undergo multiple endoscopic procedures and treatment strategies include resuscitative measures and endoscopic therapies (same para). Among all GI bleeding in patients with LVADs, 47% of the episodes originated from the upper GI tract, 22% are from the lower GI tract, 15% are from the midgut (ligament of Treitz to the ileocecal valve), and nearly 19% remain unknown. (“Etiology and pathophysiology” para 1). Other common lesions include gastritis (22%), peptic ulcer disease (13%), diverticular hemorrhage (6%), colonic polyps (5%), and colitis (4%), with the remaining causes unknown (same para). Initial management for acute GI bleeding include IV fluid resuscitation, electrolyte replacement, packed red blood cell transfusion to hemoglobin goals of 7-9 g/dL, and discontinuation of antiplatelet (acetylsalicylic acid (ASA) and P2Y12 inhibitors) and anticoagulation (Coumadin) medications (“Acute medical management” para 1). The reference concludes that the currently known/standard methods of treating GI bleeding secondary to LVAD placement such as the conservative methods of reducing anticoagulation doses and discontinuing antiplatelet and anticoagulation therapies are unsafe and not successful in most instances (“Conclusion” para 1).
MLPSC Type Affects Therapeutic Potential:
Post-dated Kozlowska et al (World J Stem Cells. 2019 Jun 26;11(6):347-374.) states that mesenchymal stromal/stem cells (MSCs) constitute a promising tool in regenerative medicine and can be isolated from different human tissues (abstract). However, their biological properties are still not fully characterized. Whereas MSCs from different tissue exhibit many common characteristics, their biological activity and some markers are different and depend on their tissue of origin (same para). MSC-based treatment is still provided as experimental procedures. The reason lies in the great diversity of MSCs, depending on their original tissue location, age of donor, methodology of isolation, and culture conditions. All these factors affect the behavior of MSC culture, making the in vivo activity of MSCs difficult to predict (Introduction, para 7).
See et al (J Cell Mol Med. 2011 Oct;15(10):2117-29) states Stromal precursor antigen (STRO)-3 has previously been shown to identify a subset of adult human bone marrow (BM)-derived mesenchymal lineage precursors, which may have cardioprotective potential. Immunoselection of STRO-3+ MPCs enriched for fibroblastic colony forming units from unfractionated BM mononuclear cells (MNCs). Compared to mesenchymal stem cells conventionally isolated by plastic adherence, MPCs demonstrated increased proliferative capacity during culture expansion, expressed higher levels of early ‘stem cell’ markers and various pro-angiogenic and cardioprotective cytokines, and exhibited greater trilineage developmental efficiency. Intramyocardial injection of MPCs into a rat model of myocardial infarction (MI) promoted left ventricular recovery and inhibited left ventricular dilatation. These beneficial effects were associated with cardioprotective and pro-angiogenic effects at the tissue level, despite poor engraftment of cells. Treatment of MI rats with MPC-conditioned medium (CM) preserved left ventricular function and dimensions, reduced myocyte apoptosis and fibrosis, and augmented neovascularization, involving both resident vascular cells and circulating endothelial progenitor cells (EPCs).
Administration route:
Post-dated Levy et al (Sci Adv. 2020 Jul 22;6(30):eaba6884; reference in IDS filed 10/28/2025) states that the behavior of MSCs including the pharmacokinetic and biological properties of the infused MSCs, can be affected by the mode of administration (“Overcoming clinical challenges from administration” para 1). Specifically, factors such as the injection site, injection device properties, and properties of the carrier materials/buffer can affect the administration of cells (Fig. 1B; same para). For example, different injection sites can cause variations in backpressure/reflux, and injection device properties (needle size/geometry) can cause variations in shear rate and shear stress during injection that are known to affect the viability of injected cells (same para). Most MSC therapies that have progressed to late-stage clinical trials have used local MSC administration (i.e., intrathecal, intralesional, and endocardial) within various clinical indications including lower back pain, perianal fistulas, and chronic heart failure (“Local administration” para 1)). Local administration of MSCs is a more controlled delivery approach, making it easier to access the disease site that often results in better therapeutic responses (same para). In ischemic stroke, for example, locally administering MSCs to the damaged site has shown to be more effective than intra-arterial and intravascular MSC injection in improving the neurological severity score (same para). However, there are still clinical challenges associated with local administration that hinder therapeutic efficacy, primarily due to insufficient retention and survival of transplanted MSCs at the site of administration. The lack of retention following local administration has been attributed to multiple issues after administration, including cell death due to the hostile environment encountered at the disease site and poor engraftment into the tissue (“Insufficient retention and survival” para 1). Some cases have shown that less than 5% of administered cells remain at the site of injection in the hours following transplantation (same para). For example, in a study using intracoronary injection of bone marrow stem cells in patients with MI, only 2.1% of radiolabeled stem cells remained at the site of injection after ~1 hour and most of the remaining signal was found primarily in the liver and spleen (same para). This clinical study highlights that, despite injecting MSCs directly at the damaged tissue site, retention in these regions is still a major concern and the cells that are at the target site are often no longer viable due to immune-mediated damage and apoptosis (same para). As an alternative to local delivery, systemic administration (such as intravenous injection) has limited utility due to insufficient homing to the target site as well as leading to instant blood-mediated inflammatory reaction (IBMIR) and insufficient residence time at the target site (“Systemic administration” para 1). When MSCs are delivered systemically, a key factor for exerting maximal therapeutic benefit is their ability to remain in circulation for long enough to deliver therapeutic payloads to the damaged tissue (“Insufficient homing” para 1). However, it is well known that intravenously administered MSCs are immediately concentrated in the lung capillaries and phagocytosed by monocytes within 24 hours (same para). This limits the MSC’s ability to deliver therapeutic payloads to the host environment via secreted paracrine factors to a short period of time following injection and limits cell homing to target tissues (same para).
The art shows that GI bleeding can result secondarily due to many disease processes, currently known and well-studied treatments are unsuccessful, biological activity and markers of MSCs are different and depend on their tissue of origin, STRO-3 MLPSCs exhibit left ventricular recovery compared to other MSCs despite poor engraftment, and that the administration of MSCs via local and systemic means affects the behavior of the MSCs and results in limited honing to the site of disease/injury and inefficient treatment. These, in combination, make it unpredictable for one of ordinary skill in the art to know whether the claimed method of administering mesenchymal lineage precursor or stem cells would in fact prevent or treat GI bleeding (either primary or secondary to another disease process or intervention).
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art. While the results presented in the art do not necessarily preclude Applicant’s hypothesis, they certainly fail to support it in its totality that MLPSCs can treat GI bleeding in any subjects via any administration route. Applicants do not provide the details of how MLPSCs could be used to prevent or treat any subjects with GI bleeding other than reducing incidence of GI bleeding secondary to LVAD placement nor is there a reduction to practice the instant method of preventing GI bleeding or treating GI bleeding in any other subject than LVAD recipients via direct myocardium injection provided in the instant specification with the claimed MLPSCs. Consequently, the prior and post-filling art, when combined with the lack of any disclosed direct experimental test of Applicant’s hypothesis, shows that one of ordinary skill would have no basis to reasonably predict or conclude that the MLPSCs could be used in the claimed method of treating all subjects in need having GI bleeding via all administration routes. It is noted that, though not controlling, the lack of working examples is a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them (Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971)).
In essence, the specification merely presents an idea of, and leaves it entirely up to the practitioner to determine, whether the method would produce a therapeutically relevant effect in a subject having a disease other than those who have undergone LVAD implantation, and if so, how to carry out the claimed method. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
One of ordinary skill in the art before the effective filing date of the instantly claimed invention would require to perform trial and error experimentation to select an appropriate population of subjects in need, trial and error experimentation to select appropriate subpopulation of subjects in need experiencing GI bleeding, trial and error experimentation to administer MLPSCs via various administration routes to prevent or treat GI bleeding in the subpopulation of subjects in need, and trial and error experimentation to determine whether the administration of the MLPSCs would be able to prevent or treat different types of GI bleeding in vivo.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-5, 7-8, 14, and 19-20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hughes (“Stem Cell Adjunct to LVAD Trial Negative, But Intriguing”, Medscape, 15 Nov 2018; Retrieved from the Internet 21 Aug 2026. Accessed from https://www.medscape.com/viewarticle/904921?form=fpf; reference in IDS filed 10/28/2025) as evidenced by Jakovljevic et al (J Am Coll Cardiol. 2017 Apr 18;69(15):1924-1933; reference in IDS filed 10/28/2025).
Regarding claim 1, 5, and 7, Hughes discloses a trial investigating the injection of allogeneic mesenchymal progenitor cells (i.e., mesenchymal stem cells) to enhance myocardial recovery in patients who have received a left ventricular assist device, which showed improvement in patients with ischemic heart failure (para 2).
Regarding claim 2, Hughes teaches that there was a large reduction in gastrointestinal bleeding in the patients who received the stem cells compared to control subjects (same para).
Regarding claim 3 and 8, Hughes states that LVADs often induce systemic inflammation (para 4) and that mesenchymal stem cells can strengthen myocardium, have anti-inflammatory role through secretion of anti-inflammatory proteins and that the systemic anti-inflammatory role contributed to the observed reduction in bleeding (para 6).
Regarding claim 14 and 19-20, Hughes discloses that the study evaluated intramyocardial injection of 150 million bone marrow derived mesenchymal progenitor cells and enrolled 159 patients with advanced heart failure from ischemic or non-ischemic etiology undergoing LVAD implantation (para 12 and 13) injection.
The teachings of Jakovljevic are relied upon as providing evidence that LVADs have been used as an effective therapeutic option in patients with advanced heart failure either as a bridge to transplantation, as destination therapy, or in some patients as a bridge to recovery (abstract). This shows that LVAD implantation in Hughes would inherently be bridge to transplantation and destination therapy and anticipates instant claim 4.
Accordingly, Hughes anticipates the instantly claimed invention of claims 1-5, 7-8, 14, and 19.
Claim(s) 1, 12-13, 18, and 20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu et al (Exp Ther Med, 20 Sept 2016; 12(5): 2983-2989; reference in IDS filed 10/28/2025).
Regarding claim 1, Hu discloses the investigation of the safety and therapeutic effect of MSCs derived from human umbilical cord on moderate to severe ulcerative colitis (abstract)
Regarding claim 1and 12, the reference continues to teach that the symptoms of ulcerative colitis commonly include bloody diarrhea, rectal bleeding or rectal urgency (“Introduction” para 1).
Regarding claim 13, 18, and 20, Hu teaches that patients in group I were treated with MSC infusions twice besides the base treatment of stable doses of aminosalicylates, one via injection into the veins in the back of the hand, and the other injected into the superior mesenteric artery by interventional catheterization, with a 7-day interval (“Materials and methods: Treatment”, para 1).
Accordingly, Hu anticipates the instantly claimed invention of claims 1, 12-13, and 18.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hughes in view of Jakovljevic et al (J Am Coll Cardiol. 2017 Apr 18; 69(15):1924-1933; reference in IDS filed 10/28/2025).
Claim 6 specifies the heart failure is due to hypertension, cardiomyopathy, myocarditis, obesity, or diabetes.
The teachings of Hughes was recited in the above 35 U.S.C. 103 rejection as applied to claim 5 of which claim 6 depends. The teachings will not be repeated here.
Hughes does not teach that the LVAD patients had heart failure due to hypertension, cardiomyopathy, myocarditis, obesity, or diabetes.
Jakovljevic teaches whether patients undergoing LVAD bridge-to-recovery protocol can achieve cardiac and physical functional capacities equivalent to those of healthy controls (abstract, “Objectives”). All of the LVAD patients were implanted with a continuous blood flow LVAD and all had dilated cardiomyopathy (“Study participants” para 3). This shows that heart failure that results in LVAD placement can be due to cardiomyopathy.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer mesenchymal stem cells to patients with LVAD implant due to heart failure to reduce GI bleeding as taught by Hughes, where the heart failure is due to cardiomyopathy as taught by Jakovljevic, to arrive at the instantly claimed invention. Hughes shows that LVAD-implanted patients have heart failure and can have reduced GI bleeding when administered mesenchymal stem cells. Jakovljevic shows that heart failure which requires LVAD implantation includes dilated cardiomyopathy. It would have been prima facie obvious to try, from a finite number of identifiable, predictable solutions, for one of ordinary skill in the art to select patients who have LVAD implantations due to heart failure associated with cardiomyopathy because LVAD patients (regardless of what caused the LVAD implantation) have increased risk of GI bleeding with a reasonable expectation of success as taught by the prior art.
Claim(s) 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hughes as applied to claims 1-5, 7-8, 14, and 19, and further in view of Geisen et al (Eur J Cardiothorac Surg. 20 Feb 2008; 33(4):679-84; reference in IDS filed 10/28/2025).
The teachings of Hughes was recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claim 10-11 depends. The teachings will not be repeated here.
Hughes does not teach that the GI bleeding is associated with:
Aortic stenosis,
von Willebrand's disease, or
epistaxis.
Regarding (i)-(iii), Geisen teaches that bleeding remains a leading complication of VAD support and may be symptomatic of acquired von Willebrand disease (AVWD) (abstract and “Introduction” para 1). Gastrointestinal bleeding not related to drug therapy has been observed in patients with aortic stenosis and has been attributed to AVWD (p. 683, para 2). Epistaxis, gastrointestinal, and surgical hemorrhage are observed frequently in VAD-implanted patients due to AVWD caused by high shear forces from the VADs (“Introduction” para 2). This shows that acquired von Willebrand disease and epistaxis is resultant of VAD implantation.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer mesenchymal stem cells to patients with LVAD implant due to heart failure to reduce GI bleeding as taught by Hughes, where the GI bleeding is associated with aortic stenosis, von Willebrand’s disease, and epistaxis as taught by Geisen, to arrive at the instantly claimed invention. Geisen shows that acquired von Willebrand disease, aortic stenosis, and epistaxis (leading to GI bleeding) is associated with ventricular assist device implantation. It would have been well within the purview of one of ordinary skill in the art and prima facie obvious to try to reasonably select subjects who have LVAD implantations whose GI bleeding is associated with AVWD, aortic stenosis, and/or epistaxis because the high sheer forces from the LVAD causes AVWD and GI bleeding.
Claim(s) 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hughes in view of Itescu et al (WO 2016102601 A1, 22 Dec 2015; Published 30 June 2016; reference in IDS filed 10/28/2025).
The teachings of Hughes was recited in the above 35 U.S.C. 102 rejection as applied to claim 5 of which claims 15 and 16 depend. The teachings will not be repeated here.
Hughes does not teach:
that the cells are administered between about 1- and 7-days after heart failure diagnosis, or
that the MLPSCs are culture expanded from STRO-1+ MLPSCs.
Regarding (i) and (ii), Itescu teaches that mesenchymal lineage precursor or stem cells can be used to treating or preventing progressive heart failure in subjects with persistent left ventricular dysfunction (abstract). The mesenchymal stem cells are approximately 24 hours post-MI (para 0007). The reference teaches that one cause of heart failure is systolic dysfunction following a myocardial infarction (para 0070).
Regarding claim 16-17, Itescu teaches that the enriched MLPSCs are expanded in vitro by culture (i.e., culture expanded) from STRO-1+ MLPSCs (para 0060 and see claim 12 of Itescu).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer mesenchymal stem cells to patients with LVAD implant due to heart failure to reduce GI bleeding as taught by Hughes, where the cells are culture expanded from STRO-1+ cells and are administered post-heart failure as taught by Itescu, to arrive at the instantly claimed invention. Hughes shows that LVAD patients (i.e., those with severe left ventricular dysfunction) experience GI bleeding that can be treated with mesenchymal stem cells. Itescu shows that subjects with progressive heart failure due to MI and persistent left ventricular dysfunction can be given MLPSCs derived from STRO-1+ MLPSCs. One of ordinary skill would have been motivated to administer the culture expanded MLPSCs after heart failure diagnosis with a reasonable expectation of advantageously ameliorating disease symptoms (GI bleeding due to LVAD implant and heart failure due to left ventricular dysfunction) at the same time as taught by the prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 9-5.
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/G.R./Examiner, Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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