DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 05/11/2026, is acknowledged.
3. Claims 1-4, 6, 11-13, 15-17, 19, 23-24, 26-31, 36-38, 44-45, 48 and 50-51 are pending.
4. Applicant’s election without traverse of Group IV, claims 1-4, 6, 23-24, 36-38, 44-45, 48, 50-51 directed to a method of treating heart failure associated with aging, comprising administering to a patient in need thereof an effective amount of an ActRII-ALK4 antagonist, wherein the ActRII-ALK4 antagonist is a heteromultimer polypeptide, wherein the heteromultimer polypeptide comprises an ActRIIB polypeptide, and the species SEQ ID NO: 5, filed on 05/11/2026, is acknowledged.
5. Claims 11-13, 15-17, 19, and 26-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-4, 6, 23-24, 36-38, 44-45, 48, 50-51 are under examination as they read on a method of treating heart failure associated with aging, comprising administering to a patient in need thereof an effective amount of an ActRII-ALK4 antagonist, wherein the ActRII-ALK4 antagonist is a heteromultimer polypeptide, wherein the heteromultimer polypeptide comprises an ActRIIB polypeptide, and the species SEQ ID NO: 5.
7. Applicant’s IDS, filed 02/02/2024, 01/08/2025, 05/09/2025, 05/08/2026 is acknowledged.
8. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
9. Claim 50 is rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
A. The recitation of “S26T” in claim 50 substitution with respect to SEQ ID NO: 2 is ambiguous because SEQ ID NO: 2 has T26.
10. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
11. Claims 1-4, 6, 23-24, 36-38, 44-45, 48, 50-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 encompasses a broad genus of ActRII-ALK4 antagonist in the treatment of heart failure associated with aging.
Claim 23 encompasses a broad genus of a broad genus of hetromultimer polypeptide
Claims 24, 36, 44-45 encompass a broad genus of ActRIIB polypeptides.
Claims 37-38 encompass a broad genus of ActRIIB polypeptide comprises up to 10% modification in the in a sequence that begins at any one of amino acids of 20-29 and ends at one of amino acid residues 109-134 of SEQ ID NO:2, aa 29-131, 25-131, 20-134 of SEQ ID NO: 2 or SEQ ID NO: 53, 388, 380.
Claim 48 encompasses a genus of fusion polypeptides comprising up to 10% variation in SEQ ID NO: 5.
Claims 50-51 encompasses a genus of ActRIIB polypeptide comprising up to 179 substitutions
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of treating heart failure associated with aging. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification discloses that while not wishing to be bound to any particular mechanism, it is expected that the effects of the ActRIIB-ALK4 heterodimer on heart failure is caused primarily by antagonizing ligand-signaling as mediated by one or more ligands that bind to the ActRIIB-ALK4 heterodimer protein including, but not limited to, activin A, activin B, GDF8, GDF11, BMP6, and/or BMP10 (referred to herein as “ActRII-ALK4 ligands” or “ActRII-ALK4 ligand”). Regardless of the mechanism, it is apparent from the data presented herein that ActRIIB-ALK4 heterodimers have significant positive effects in ameliorating various complications associated with heart failure and further suggests that other ActRII-ALK4 antagonists may also be useful in treating heart failure associated with aging.
Besides SEQ ID NO: 5, the specification describes the amino acid sequence of ActRIIA and ActRIIB and ALK4, the specification does not describe any correlation between the sequence and the structure of any agent that that treat heart failure associated with aging.
The specification describes a method of screening mutants for functionally active ActRIIB ([0455] , [0462], [0463], [0465] ) or for treating heart failure ([0753]- [0757]), however, there is no information regarding what structural features would likely be associated with such the treating heart failure associated with aging. Thus, the specification does not disclose a correlation between an ActRII-ALK4 or ActRIIB- ALK4 antagonist for treating heart failure associated with aging and the structure of a putative antagonist/polypeptide.
The level of skill and knowledge in the art is that there are no known ActRII(B)-ALK4 that treat heart failure associated with aging and no known correlation between any structural component and the ability to treat heart failure associated with aging. Thus, the disclosure does not allow one of skill in the art to visualize or recognize the structure of any antagonist/polypeptide required to practice the claimed method. Accordingly, one of ordinary skill in the art would conclude that the applicant would not have been in possession of the claimed method of using a ActRII(B)-ALK4 antagonist/polypeptide that treat heat failure associated with aging because an antagonist/polypetide possessing the desired activity required to practice the method is not adequately described and was not known in the art.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of ActRII/B-ALK4 antagonist/polypeptides having a sequence at least 90% identical to residues beginning form 20-29 and ending at residues 109-134 of SEQ ID NO: 2, or SEQ ID NO: 5 defined by amino acid sequence, falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The Federal Circuit has again recently discussed the inherent unpredictability of protein engineering in the Abbvie case, Abbvie Deutschland Gmbh & Co KG, Abbvie Bioresearch Center, Inc., and Abbvie Biotechnology, Ltd., v. Janssen Biotech In. And Centocor Biologics, LLC, Case No. 2013-1338 and 2013- 1346, C.A.Fed. ("Abbvie"). While Abbvie, similar to the previously discussed Novozymes case, is concerned with the written description requirement under §112, the Federal Circuit reiterates the inherent unpredictability of protein engineering in Abbvie: For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the '128 and '485 patents do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.
The facts of Abbvie parallel those of the instant case and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. The question is not whether one of skill knows how to generate the an ActRIIB variant and screening for the one that works, but whether the specification sufficiently describes the specific substitutions in the ActRIIB that correlate with the functions of treating HF associated with aging.
While claims 50 and 51 recites one or more substations with respect to ActRIIB polypeptide of SEQ ID NO: 2 for that antagonizes ActRII-ALK4 however the specification fails to show that introducing one or more of the recited mutations would have a selectivity to ALK4 ligand and thus antagonizing their interaction. There is no nexus between the claimed substitution(s) and ActRIIB hetromultimeric polypeptide that antagonizes ActRII-ALK4. US 20060068468 A1 demonstrates that increase the selectivity of the altered ligand-binding domain for GDF11 (and therefore, presumably, GDF8) over activin (presented with respect to ActRIIB): K74Y, K74F, K74I and D80I. The following mutations have the reverse effect, increasing the ratio of activin binding over GDF11: D54A, K55A, L79A and F82A. The overall (GDF11 and activin) binding activity can be increased by inclusion of the "tail" region or, presumably, a unstructured linker region, and also by use of a mutation such as A64R (which occurs naturally) or K74A. Other mutations that caused an overall decrease in ligand binding affinity, include: R40A, E37A, R56A, W78A, D80K, D80R, D80A, D80G, D80F, D80M and D80N.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
12. 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.
13. Claims 1, 3-4, 6, 23, 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2018/0163187.
The `187 publication teaches the use of an ALK4:ActRIIB heteromultimer as part of a treatment congestive heart failure (¶228). The `187 publication teaches antagonists of ALK4 and/or ActRIIB-binding ligands, ALK4:ActRIIB heteromultimer comprising ActRIIB-bindign ligands, or ActRIIB receptors [0355] . The claimed functional properties recited in claims 3-4 and 6 are considered inherent properties to the treatment methods in the absence of evidence to the contrary.
The reference teachings anticipate the claimed invention.
14. Claims 1 3-4, 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20170281711.
The `711 publication teaches and claims methods for treating or ameliorating of congestive heart failure in a subject, comprising administering to a subject in need thereof an effective amount of the ActRIIB-binding antibody (i.e., antagonist of ActRIIB-ALK4) (see published claims 1, 16, 40, 41).
The reference teachings anticipate the claimed invention.
12. Claim 1-4, 6, 23-24, 36-38, 44-45, 48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Roh et al (Sci. Transl. Med. 11, eaau8680 (2019), of record.
Roh et al assess the therapeutic potential of targeting ActRII signaling in heart failure (HF), they independently tested two pharmacological reagents (CDD866 and RAP-031 (i..e, SEQ ID NO: 5) capable of inhibiting a broad spectrum of ActRII ligands. Both reagents have been evaluated in early clinical trials for sarcopenia (33, 36), underscoring the translational relevance of these approaches. Both reagents consistently improved cardiac function in multiple HF models and restored function in failing hearts induced by pressure overload or a clinically relevant sarcomere mutation. These functional effects were recapitulated with two different inhibitors in three different HF models in two strains of mice and with CM-specific ActRIIB deletion in TAC (page 9, right col, 1st ¶). It is noted that TAC is a model of HfpEF which leads to systolic heart failure with a reduced ejection fraction.
Roh et al teach systemic ActRII inhibition improves systolic function in murine age-related HF models. Importantly, Roh et al examined whether ActRII inhibition could improve cardiac functional impairments seen in old C57BL/6 mice (29, 30) using amurinized version of bimagrumab (CDD866), a monoclonal anti-body (Ab) that blocks ActRIIA and ActRIIB and is currently under clinical investigation for sarcopenia (Fig. 4A) (33, 34). Similar to its effects in young mice (34), CDD866 increased skeletal muscle mass but did not significantly alter cardiac mass or blood pressure in old mice (figs. S5 and S7). CDD866 effectively blocked cardiac ActRII signaling (Fig. 4B) and reduced pulmonary congestion (Fig. 4C).CDD866 also improved subclinical LV systolic dysfunction, including measures of systolic strain and contractile reserves (Fig. 4, D and E). Because CDD866 mostly affected systolic function, which is only modestly altered in aged C57BL/6 mice, Roh et al explored its effects in an age-related model of dilated cardiomyopathy based on a known myosin heavy chain missense mutation (MHCF764L) found in humans (35).Knock-in mice heterozygous for this mutation develop progressive LV dilatation and systolic dysfunction with age. Treating these mice (21to 23 months old) with CDD866 decreased cardiac ActRII signaling (Fig. 4F) and increased FS by ~45% within 4 weeks (Fig. 4G). The marked effects of CDD866 in aged MHCF764L mice prompted us to repeat these studies with an ActRIIB-Fc fusion protein, RAP-031, (comprising claimed SEQ ID NO: 5) to ensure that the effect was not reagent specific. RAP-031 is a soluble ligand trap that blocks pathway activation by binding circulating ActRII ligands (Fig. 4A) (36). Four weeks of RAP-031 treatment induced results similar to CDD866, increasing FS by ~34% (Fig. 4H) (see page 4, both left and right col).
Roh et al teach that to confirm that the cardiac effects induced by CDD866 in TAC were not strain or reagent specific, Roh et al repeated these studies in FVB mice with RAP-031. Although the effect size was smaller, reflecting less severe cardiac dysfunction in FVB mice after TAC, RAP-031 similarly improved systolic function in TAC-induced HF (fig. S9) (p.5, right col., 1st ¶). Fig. S9. RAP-031 prevents and rescues cardiac dysfunction in TAC.
The claimed functional properties recited in claims 3-4, 6 are considered inherent in the absence of evidence to the contrary.
The mechanism of action does not have a bearing on the patentability of the invention if the invention was already known or obvious. Even though applicant has proposed or claimed the mechanism by which ActRII-ALK4 antagonist alleviates symptoms of heart failure does not appear to distinguish the prior art teaching the same or nearly the same methods to achieve the same end result. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145.
Therefore, it is clear that both Roh et al. and applicant administer the same composition comprising the same heteromultimer polypeptide of RAP-031/ActRIIB-Fc to the same patient to achieve the same results. The prior art and applicant have suggested different mechanisms. It is acknowledged that applicant now recites and believes in a different mechanism of action than the prior art. However, the instant methods do not negate or preclude the mechanism of action indicated by the prior art nor does applicant provide objective evidence to distinguish the prior art from the claimed invention.
Claims 37 and 38 are included because ActRIIB comprises residues 20-134 of SEQ ID NO: 2.
The reference teachings anticipate the claimed invention.
13. Claim 1-4, 6, 23-24, 36-38, 44-45, 48 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by US 20200087367 A1.
The `367 publication teaches and claims methods of reducing the risk of death and/or hospitalization of a patient having heart failure, comprising administering to a patient in need thereof an effective amount of a BMP antagonist (published claims 1, 4, 7, 10 129-130), wherein the method increases cardiac ejection fraction (published claims 21-22, 39-41), wherein the method reduces diastolic blood pressure (published claims 31-32) wherein the BMP antagonist is wherein the BMP antagonist is an ActRIIB polypeptide (published claim 78), wherein the ActRIIB polypeptide is selected from the group consisting of a polypeptide comprising amino acids 29-109, 25-131 of SEQ ID NO: 1, SEQ ID NO: 2, 3, 5, 6, 65, 133 (published claim 79), wherein the ActRIIb polypeptide is a fusion protein comprising an immunoglobulin Fc domain, wherein the immunoglobulin Fc domain is an IgG1 Fc immunoglobulin domain (published claims 92-96), wherein the fusion protein is an ActRIIB-Fc fusion protein selected from the group consisting of SEQ ID NO: 58 (i.e., ActRIIB-hFc, claimed SEQ ID NO: 5), 60, 63, 64, 66, 123, 131, 132 (published claims 97-99), wherein the patient has one or more types of heart failure selected from the group consisting of: heart failure due to left ventricular dysfunction, heart failure with normal ejection fraction, aortic stenosis heart failure, acute heart failure, chronic heart failure, congestive heart failure, congenital heart failure, compensated heart failure, decompensated heart failure, diastolic heart failure, systolic heart failure, right-side heart (ventricle) failure, left-side heart (ventricle) failure, forward heart failure, backward heart failure, high output heart failure, low output heart failure, and myocardial edema, wherein the patient has at least class I heart failure in accordance with the New York Heart Association (NYHA) functional classification, wherein the patient has class II, class III, or class IV heart failure in accordance with the NYHA functional classification, wherein the patient has at least stage A heart failure in accordance with the American College of Cardiology/American Heart Association working group (AAC) functional classification, wherein the patient has stage B, stage C, or stage D heart failure in accordance with the ACC functional classification, wherein the method improves the patient's heart failure score in accordance with the ACC functional classification system by at least one stage (e.g., improvement from stage D to stage C heart failure, from stage D to stage B heart failure, from stage D to stage A heart failure, from stage C to stage B heart failure, from stage C to stage A heart failure, or from stage B to stage A heart failure), wherein the method prevents or delay progression of the patient's heart failure score in accordance with the ACC functional classification system by at least one stage (e.g., prevents or delays progression from stage A to stage B heart failure, delays progression from stage A to stage C heart failure, delays progression from stage A to stage D heart failure, delays progression from stage B to stage C heart failure, delays progression from stage B to stage D heart failure, or delays progression from stage C to stage D heart failure (See published claims 42-56).
It is noted that hospitalization patients with heart failure (HF) are associated with individuals over 65 years old.
[0363] A variant of ActRIIB(20-134) having a leucine-to-aspartate substitution at position 79 in SEQ ID NO:1 was fused to a Fc domain with a linker in between. The construct is referred to as ActRIIB(L79D 20-134)-hFc. Alternative forms with a glutamate rather than an aspartate at position 79 performed similarly (L79E) in binding assays.
The reference teachings anticipate the claimed invention.
14. 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.
15. Claims 1-4, 6, 23-24, 36-38, 44-45, 48, 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Roh et al (Sci. Transl. Med. 11, eaau8680 (2019) in view of Lim GB (Nature Reviews Cardiology, 16: 258, 2019, of record) and optionally US 20180163187 and US2010316644 or WO2018067874.
Roh et al teachings have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation that the
inhibitor is ACTRII-ALK4 antagonist in claim 1 and the ActRIIB-Fc is SEQ ID NO: 5 in claim 48.
Lim GB teaches that in mice, increasing the circulating levels of activin A, a ligand for
ACTRII, increased cardiac ACTRII signalling and impaired cardiac function. Of note, a
murinized version of bimagrumab (CDD866), a monoclonal antibody that blocks ACTRIIA
and ACTRIIB improved subclinical left ventricular systolic dysfunction in aged mice. In a
mouse model of HF induced by transverse aortic constriction (TAC), CDD866 improved
systolic function and reduced pulmonary oedema. The activin receptor type 2 (ACTRII)
pathway is activated in ageing and heart failure (HF), and inhibition of this catabolic pathway
is a potential therapeutic target for HF. "What's particularly exciting to us is that 'human
versions' of the two inhibitors we used for these studies have already been used in early-phase
clinical trials for other indications, so we're hopeful that they - or other inhibitors - could
be re-purposed for HF," comments Anthony Rosenzweig, senior investigator on the article
now published in Sci. Transl Med.
The `187 publication teach an ALK4:ActRIIB heteromultimer can be used for regulating body fat content in an animal and for treating or preventing conditions related thereto, and particularly, health-compromising conditions related thereto. For example, an ALK4:ActRIIB heteromultimer may be used to treat or prevent a disorder or condition including congestive heart failure [0228], [0235], [0252].
The `644 publication teach human activin type-IIB receptor (20-134)-IgG1 Fc fusion protein used in pharmaceutical preparation for treating disorder associated with muscle loss and metabolic disorder. The present ActRIIB-hFc sequence is not shown in the specification but is derived from human ActRIIB precursor protein given in page 5 and ActRIIB(25-131)-hFc fusion protein given in figure 1 respectively (see Examples 1-2, page 2, 56, ¶¶1-2).
The `874 publication teaches TPA-ActRIIB-G1Fc fusion protein, SEQ 6 (see page 167, lines 24+).
Qy 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 26 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 85
Qy 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 86 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 145
Qy 121 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 146 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 205
Qy 181 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 206 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 265
Qy 241 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 266 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 325
Qy 301 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 343
|||||||||||||||||||||||||||||||||||||||||||
Db 326 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 368
The `874 publication claims a heteromultimer protein comprising a first ActRIIB polypeptide and a second ActRIIB polypeptide, wherein the first ActRIIB polypeptide comprises an amino acid sequence that is at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%), 98%), 99%), or 100% identical to an amino acid sequence that begins at any one of amino acid 20-29 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) of SEQ ID NO: 2 and ends at any one of amino acid 109-134 (e.g., 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134) of SEQ ID NO: 2 and one or more amino acid substitutions at a position of SEQ ID NO: 2 selected from the group consisting of: A24, K74, R64, P129, P130, E37, R40, D54, R56, W78, D80, and F82, wherein the second ActRIIB polypeptide comprises an amino acid sequence that is at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence that begins at any one of amino acid 20-29 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) of SEQ ID NO: 2 and ends at any one of amino acid 109-134 (e.g., 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134) of SEQ ID NO: 2, and wherein the first ActRIIB polypeptide comprises a different amino acid sequence compared to the second ActRIIB polypeptide (published claim 44), wherein the first ActRIIB polypeptide comprises one or more amino acid substitution with respect to the amino acid sequence of SEQ ID NO: 2 selected from the group consisting of: A24N, K74A, R64K, R64N, K74A, L79A, L79D, L79E, L79P, P129S, P130A, P130R, E37A, R40A, D54A, K55A, R56A, K74F, K74I, K74Y, W78A, D80A, D80F, D80G, D80I, D80K, D80M, D80M, D80N, D80R, and F82A, wherein the first ActRIIB-Fc fusion protein and/or second ActRIIB-Fc fusion protein further comprises a linker domain positioned between the ActRIIB polypeptide domain and the one or more heterologous domains or Fc domain (Fig. 10, claims 49-56).
Those of skilled in the art would have had a reason to TPA-ActRIIB-G1Fc taught by `644 and `874 publications as a substitute for the ActRIIB-Fc /RAP-031 in the treatment of HF associated with aging taught by Roh et al because like the ActRIIB-Fc /RAP-031, TPA-ActRIIB-G1Fc is the human version/analog of RAP-031. Substituting a known element for another, to yield the known result, is obvious. See KSR, 550 U.S. at 416, 421 (2007).
"[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result." KSR Int'l v. Teleflex Inc., 550 U.S. 398,416 (2007).
"Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties." In re Merck & Co., Inc., 231 USPQ 375,379.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
16. Claims 1-4, 6, 23-24, 36-38, 44-45, 48, 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over US 20200087367 A1 in view of Lim GB (Nature Reviews Cardiology, 16: 258, 2019, of record).
The teachings of the `367 publication have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation of HF associated with ageing in claim 1.
Lim GB teaches that in mice, increasing the circulating levels of activin A, a ligand for
ACTRII, increased cardiac ACTRII signalling and impaired cardiac function. Of note, a
murinized version of bimagrumab (CDD866), a monoclonal antibody that blocks ACTRIIA
and ACTRIIB improved subclinical left ventricular systolic dysfunction in aged mice. In a
mouse model of HF induced by transverse aortic constriction (TAC), CDD866 improved
systolic function and reduced pulmonary oedema. The activin receptor type 2 (ACTRII)
pathway is activated in ageing and heart failure (HF), and inhibition of this catabolic pathway
is a potential therapeutic target for HF. "What's particularly exciting to us is that 'human
versions' of the two inhibitors we used for these studies have already been used in early-phase
clinical trials for other indications, SO we're hopeful that they - or other inhibitors - could
be re-purposed for HF," comments Anthony Rosenzweig, senior investigator on the article
now published in Sci. Transl Med.
Those of skill in the art would have had a reason to target the HF associated with ageing with the
ActRIIA-hFc fusion protein (claimed/referenced SEQ ID NO: 5/ 58) taught by the `367publication because like CDD866, ActRIIA-Fc
would block ACTRIIA to its ligand activin A.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
17. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
18. Claims 1-4, 6, 23-24, 36-38, 44-45, 48-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 300-319 of copending Application No. 18010888 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the `888 application are directed to methods of treating heart failure (HF) in a patient in need thereof, comprising administering to the patient an effective amount of an ActRIIB-ALK4 antagonist, wherein the ActRIIB-ALK4 antagonist is a heteromultimer comprising an ActRIIB polypeptide and an ALK4 polypeptide, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to an amino acid sequence of SEQ ID NO: 2 or wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to amino acids 25-131 of SEQ ID NO: 2, wherein the ALK4 polypeptide comprises an amino acid sequence that is at least 90% identical to an amino acid sequence of SEQ ID NO: 84 or wherein the ALK4 polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, wherein the heteromultimer comprises an ActRIIB fusion polypeptide comprising an ActRIIB polypeptide domain and one or more heterologous domains and/or an ALK4 fusion polypeptide comprising an ALK4 polypeptide domain and one or more heterologous domains, wherein the ActRIIB or ALK4 fusion polypeptide further comprises a linker domain positioned between the polypeptide domain and the one or more heterologous domains selected from: TGGG, TGGGG, SGGGG, GGGGS, GGG, GGGG, SGGG, and GGGGS, wherein the one or more heterologous domains is an Fc domain, wherein the ALK4 fusion polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 92 or SEQ ID NO: 93, wherein the ActRIIB fusion polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 402 or SEQ ID NO: 403, wherein the heart failure is selected from genetic cardiomyopathy, dilated cardiomyopathy (DCM) or heart failure with preserved ejection fraction (HFpEF), wherein the patient has;i. normal left ventricular ejection fraction (LVEF) and an LVEF of >50%;ii. reduced LVEF and an LVEF of <40%;iii. mid-range LVEF and an LVEF of between about 40% and about 49%;iv diastolic dysfunction of the left ventricle (LV); or v. systolic dysfunction of the left ventricle (LV), wherein the patient has elevated levels of natriuretic peptides, wherein the heart failure is heart failure with mid-range ejection fraction (HFmrEF) or reduced ejection fraction (HFrEF), wherein the method decreases troponin levels in the patient by at least 1%, wherein the method decreases left ventricular hypertrophy in the patient by at least 1%, wherein the method increases the patient's LV diastolic function by at least 5%, wherein the method increases ejection fraction in the patient by at least 1%, wherein the method increases the patient's cardiac output by at least 5%. The `888 application claims methods of treating heart failure (HF) in a patient in need thereof, comprising administering to the patient an effective amount of an ActRIIB-ALK4 heteromultimer, wherein the heteromultimer comprises (1) an ActRIIB fusion polypeptide comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 402 or SEQ ID NO: 403; and(2) an ALK4 fusion polypeptide comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 92 or SEQ ID NO: 93.
A method of treating, preventing, or reducing the progression rate and/or severity of one or more comorbidities of heart failure, comprising administering to a patient in need thereof an effective amount of an ActRIIB-ALK4 antagonist.
The specification of the `888 application teaches that the prevalence of heart failure (HF) depends on the definition applied, but it affects approximately 1-2% of the adult population in developed countries, rising to >10% among people 70 years of age. Among people 65 years of age presenting to primary care with breathlessness on exertion, one in six will have unrecognized HF (mainly HFpEF). The lifetime risk of HF at age 55 years is 33% for men and 28% for women (see 1st page under Background). Susceptibility to HF is also heritable as a complex trait, and having a parent with HF who is <75 years of age was found to be a significant the risk factor for development of HF (page 232).
Alingment between claimed SEQ ID NO: 5 and co-pending SEQ ID NO: 402
Query Match 99.4%; Score 1896; DB 1; Length 368;
Best Local Similarity 99.4%;
Matches 341; Conservative 0; Mismatches 2; Indels 0; Gaps 0;
Qy 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 26 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 85
Qy 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 86 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 145
Qy 121 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 146 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 205
Qy 181 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 206 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 265
Qy 241 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 300
||||||||| ||||||||||| ||||||||||||||||||||||||||||||||||||||
Db 266 EPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 325
Qy 301 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 343
|||||||||||||||||||||||||||||||||||||||||||
Db 326 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 368
Alingment between claimed SEQ ID NO: 5 and co-pending SEQ ID NO: 403
Query Match 99.4%; Score 1896; DB 1; Length 343;
Best Local Similarity 99.4%;
Matches 341; Conservative 0; Mismatches 2; Indels 0; Gaps 0;
Qy 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
Qy 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 120
Qy 121 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 180
Qy 181 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 240
Qy 241 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 300
||||||||| ||||||||||| ||||||||||||||||||||||||||||||||||||||
Db 241 EPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 300
Qy 301 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 343
|||||||||||||||||||||||||||||||||||||||||||
Db 301 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 343
.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19. Claims 1-4, 6, 23-24, 36-38, 44-45, 48-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 13-15, 17-21, 23-24, 26-28, 30, 32, 34, 36-38, 41, 44-48 and 50-53 of copending Application No. 18549474 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the `888 application are directed to methods of treating heart failure associated with diabetic cardiomyopathy, comprising administering to a patient in need thereof an effective amount of an ActRII-ALK4 antagonist, wherein the patient is obese, or has at least one of diabetes, left ventricular (LV) hypertrophy, diastolic dysfunction, and decreased ventricular relaxation and increased filling pressures, wherein the heart failure is heart failure associated with preserved ejection fraction (HFpEF), wherein the method decreases LV hypertrophy; improves diastolic dysfunction; increases ventricular relaxation and decreases filling pressures; decreases ratio of early diastolic transmitral flow to early diastolic mitral annular tissue velocity (E/e' ratio); or decreases brain natriuretic peptide (BNP) levels in the patient, wherein the ActRII-ALK4 antagonist is a polypeptide heteromultimer, wherein the heteromultimer comprises an ActRIIB polypeptide and an ALK4 polypeptide or an ActRIIB polypeptide and an ALK7 polypeptide, wherein the ActRII-ALK4 antagonist is a heteromultimer that comprises an ActRIIB polypeptide, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to an amino acid sequence that begins at any one of amino acid residues 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 of SEQ ID NO: 2 and ends at any one of amino acid residues 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, or 134 of SEQ ID NO: 2, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to amino acids 29-109, 25-131, or 20-134 of SEQ ID NO: 2, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 53, SEQ ID NO: 388, or SEQ ID NO: 389, wherein the ActRIIB polypeptide is a fusion polypeptide comprising an ActRIIB polypeptide domain and one or more heterologous domains, wherein the fusion polypeptide is an ActRIIB-Fc fusion polypeptide, wherein the fusion polypeptide further comprises a linker domain positioned between the ActRIIB polypeptide domain and the one or more heterologous domains, wherein the linker domain is selected from: TGGG, TGGGG, SGGGG, GGGGS, GGG, GGGG, SGGG, and GGGGS, wherein the fusion polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 12, wherein the ActRIIB polypeptide comprises an amino acid sequence as set forth in SEQ ID NO:2 with one or more amino acid substitutions with respect to the amino acid sequence of SEQ ID NO: 2 selected from the group consisting of: A24N, S26T, N35E, E37A, E37D, L38N, R40A, R40K, S44T, L46V, L46I, L46F, L46A, ESOK, ESOP, ESOL, E52A, E52D, E52G, E52H, E52K, E52N, E52P, E52R, E52S, E52T, E52Y, Q53R, Q53K, Q53N, Q53H, D54A, K55A, K55D, K55E, K55R, R56A, L57E, L57I, L57R, L57T, L57V, Y60D, Y60F, Y60K, Y60P, R64A, R64H, R64K, R64N, N65A, S67N, S67T, G68R, K74A, K74E, K74F, K74I, K74R, K74Y, W78A, W78Y, L79A, L79D, L79E, L79F, L79H, L79K, L79P, L79R, L79S, L79T, L79W, D80A, D80F, D80G, D80I, D80K,D80M, D80N, D80R, F82A, F82D, F82E, F82I, F82K, F82L, F82S, F82T, F82W, F82Y, N83A, N83R, T93D, T93E, T93G, T93H, T93K, T93P, T93R, T93S, T93Y, E94K, Q98D, Q98E, Q98K, Q98R, V99E, V99G, V99K, E1O5N, F108I, F108L, F108V, F108Y, E111D, E111H, E111K, 111N, E111Q, E111R, R112H, R112K, R112N, R112S, R112T, A119P, A119V, G120N, E123N, P129N, P129S, P130A, P130R, and A132N, wherein the ActRIIB polypeptide comprises an amino acid substitution that is K55E with respect to the amino acid sequence of SEQ ID NO: 2, wherein the ActRIIB polypeptide comprises an amino acid substitution that is L79S with respect to the amino acid sequence of SEQ ID NO: 2, wherein the ActRIIB polypeptide comprises an amino acid sequence as set forth in SEQ ID NO:2 with one or more amino acid substitution substitutions with respect to the amino acid sequence of SEQ ID NO: 2 selected from the group consisting of: L38N, E5OL, E52D, E52N, E52Y, L57E, L57I, L57R, L57T, L57V, Y60D, G68R, K74E, W78Y, L79E, L79F, L79H, L79R, L79S, L79T, L79W, F82D, F82E, F82I, F82K, F82L, F82S, F82T, F82Y, N83R, E94K, and V99G.
Alignment of claimed SEQ ID NO: 5 and co-pending SEQ ID NO: 5
Qy 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
Qy 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTH 120
Qy 121 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 180
Qy 181 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 240
Qy 241 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 300
Qy 301 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 343
|||||||||||||||||||||||||||||||||||||||||||
Db 301 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 343
Alignment of claimed SEQ ID NO: 5 and co-pending SEQ ID NO: 53
Qy 6 ETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNC 65
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNC 60
Qy 66 YDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPT 112
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPT 107
Alignment of claimed SEQ ID NO: 5 and co-pending SEQ ID NO: 388
Qy 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWL 60
|||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||
Db 1 GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWANSSGTIELVKKGCWL 60
Qy 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPT 115
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPT 115
The application claims anticipate the claimed invention.
20. No claim is allowed.
21. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) US 20200031940 A1
The `940 claims:
14. A method for treating and/or preventing heart failure, said method comprising administering an effective amount of an ActRII receptor antagonist to a subject who has heart failure or who is at risk for developing heart failure wherein the heart failure is caused by, or associated with, at least one of: valvular heart disease, coronary artery disease, hypertension, diabetes, aging, arrhythmia, peripartum cardiomyopathy, stress cardiomyopathy, toxic or infectious agents, genetic cardiomyopathy or idiopathic dilated cardiomyopathy.
22. A method of treating a structural and/or functional cardiac abnormality associated with a condition selected from the group consisting of: valvular heart disease, coronary artery disease, hypertension, diabetes, aging, arrhythmia, peripartum cardiomyopathy, stress cardiomyopathy, genetic cardiomyopathy and idiopathic dilated cardiomyopathy, said method comprising administering an effective amount of an ActRII receptor antagonist to a subject having said structural and/or functional cardiac abnormality associated with said condition, wherein said valvular heart disease is aortic stenosis and wherein the aortic stenosis is accompanied by frailty and/or sarcopenia.
31. A method according to claim 29, wherein the ActRII receptor antagonist is an anti-ActRII antibody that binds to an epitope of ActRIIB consisting of amino acids 19-134 of SEQ ID NO: 181 (SEQ ID NO: 182).
46. A method according to claim 45, wherein said heart failure is heart failure with reduced ejection fraction.
47. A method according to claim 45, wherein said heart failure is heart failure with preserved ejection fraction.
(ii) US 20200087367 A1
The `367 claims:
8. The method of any one of claims 1-75, wherein the BMP antagonist is an ActRIIB polypeptide.
79. The method of claim 78, wherein the ActRIIB polypeptide is selected from the group consisting of: a. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 29-109 of SEQ ID NO: 1; b. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 25-131 of SEQ ID NO: 1; c. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2; d. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3; e. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5; f. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6; g. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 65; and h. a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 133.
92. The method of any one of claims 76-91 wherein the ActRIIA, ActRIIB, ALK1, endoglin, or BMP10pro polypeptide is a fusion protein comprising an immunoglobulin Fc domain.
1. A method of reducing the risk of death and/or hospitalization of a patient having heart failure, comprising administering to a patient in need thereof an effective amount of a BMP antagonist.
3. The method of claim 1, wherein the death of the patient is from a cardiovascular event.
4. The method of claim 3, wherein the cardiovascular event is selected from the group consisting of: myocardial infarction, stroke, angina, arrhythmia, fluid retention, and progression of heart failure.
6. The method of claim 1, wherein the hospitalization of the patient is from a cardiovascular event.
7. The method of claim 6, wherein the cardiovascular event is selected from the group consisting of: myocardial infarction, stroke, angina, arrhythmias, fluid retention, progression of heart failure.
8. A method of reducing progression of heart failure in a patient, comprising administering to a patient in need thereof an effective amount of a BMP antagonist.
9. A method of reducing incidence of cardiovascular events in a patient, comprising administering to a patient in need thereof an effective amount of a BMP antagonist.
10. The method of claim 1, wherein the cardiovascular event is selected from the group consisting of: myocardial infarction, stroke, angina, arrhythmia, fluid retention, progression of heart failure.
11. The method of claim 9 or 10, wherein the cardiovascular event would result in patient hospitalization.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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June 12, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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