DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The claim listing filed on 2/19/26 is entered; no amendment is entered. Claims 300-319 are pending.
The election of dilated cardiomyopathy (DCM) as the species of heart failure in the reply filed on 2/19/26 is acknowledged. The elected species reads on each claim.
Claims 300-319 are under consideration, as they read upon the elected species.
Specification
The disclosure is objected to for the following informalities:
---At pages 15, 17, 26 and 31, these sequences lack a sequence identifier: TGGG (SEQ ID NO: 265), TGGGG (SEQ ID NO: 263), SGGGG (SEQ ID NO: 264), GGGGS (SEQ ID NO: 267), GGGG (SEQ ID NO: 262), and SGGG (SEQ ID NO: 266).
---At pages 15, 17, 26 and 31, the amino acid sequence “GGGGS” is twice included in a recited group. One instance should be deleted to avoid redundancy.
Appropriate correction is required.
Claim Objections
Claims 300-319 are objected to because of the following informalities:
In claim 300, the acronyms “ActRIIB” and “ALK4” should be accompanied by the full terminology the first time each appears in the claim; e.g., “activin receptor IIB (ActRIIB)” (page 55) and “activin receptor kinase-4 (ALK4)” (page 96).
In claim 305, these sequences lack a sequence identifier: TGGG (SEQ ID NO: 265), TGGGG (SEQ ID NO: 263), SGGGG (SEQ ID NO: 264), GGGGS (SEQ ID NO: 267), GGGG (SEQ ID NO: 262), and SGGG (SEQ ID NO: 266).
In claim 305, the sequence “GGGGS” is duplicated (lines 3 and 4).
In claim 310, line 1, the semi-colon at the end of the line should be a colon.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a), written description
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.
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.
Claims 300-319 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The invention to which the claims are directed is a method with the intended use of treating heart failure (HF), with this therapeutic effect asserted to be achieved by a single step of administering an “ActRIIB-ALK4 antagonist” to the patient. The specification teaches that “ActRIIB” refers to “a family of activin receptor type IIB” proteins (¶ 206, published application), and that “ALK4” refers to “a family of activin receptor-like kinase-4” proteins (¶ 277). The specification provides working examples in support of the claimed invention, which teach the following superior properties with respect to the heterodimer comprising an ActRIIB polypeptide-Fc fusion linked to an ALK4 polypeptide-Fc fusion as compared to an ActRIIB-Fc homodimer:
“…ActRIIB-Fc:ALK4-Fc heterodimer is a more selective antagonist of activin A, activin B, GDF8, and GDF11 compared to ActRIIB-Fc homodimer. Accordingly, an ActRIIB-Fc:ALK4-Fc heterodimer will be more useful than an ActRIIB-Fc homodimer in certain applications where such selective antagonism is advantageous. Examples include therapeutic applications where it is desirable to retain antagonism of one or more of activin A, activin B, activin AC, GDF8, and GDF11 but minimize antagonism of one or more of BMP9, BMP10, GDF3, and BMP6” (¶ 908, Example 13).
The working examples further provide support for the claimed method with respect to treatment of heart failure, concluding in Example 16 that the “data demonstrate that ActRIIB-Fc:ALK4-Fc is effective to ameliorate various morphological and functional deficits during left heart remodeling in a murine model of HFrEF (Mdx model). In particular, LV end systolic diameter was significantly reduced in ActRIIB-Fc:ALK4-Fc treated mice compared to untreated groups, indicating that ActRIIB-Fc:ALK4-Fc improved LV contractility” (¶ 942). These results are also supported by the post-filing date publication of Li et al, 2022 (FEBS Letters. 596. 3145-3158), which includes each of the inventors among its authors.
The specification teaches that the term “ActRII-ALK4 antagonist” refers to “a variety of agents that may be used to inhibit signaling by one or more ActRII-ALK4 ligands including, for example, antagonists that inhibit one or more ActRII-ALK4 ligands (e.g., activin A, activin B, GDF8, GDF11, BMP6, and/or BMP10); antagonists that inhibit one or more ActRII-ALK4 ligand associated receptors (e.g., ActRIIA, ActRIIB, ALK4, and ALK7); and antagonists that inhibit one or more downstream signaling components (e.g., Smad proteins such as Smads 2 and 3)”. Thus, the term “ActRIIB-ALK4 antagonist” is defined functionally without being limited to any particular molecular structure, and thus broadly encompasses any type of structure, such as a polypeptide, antibody, nucleic acid, small molecule, carbohydrate, lipid, inorganic molecule or other.
The claims further expressly recite, in dependent claim 301, that the antagonist can be a “heteromultimer comprising an ActRIIB polypeptide and an ALK4 polypeptide”. This claim encompasses ActRIIB and ALK4 polypeptides having any amino acid sequence. Further dependent claims limit the amino acid sequences of the ActRIIB and ALK4 polypeptides to sequences defined with respect to reference sequences; e.g., claims 302, 303, 307 and 308. Thus, the claims are directed to several genera, including a broad genus of ActRIIB-ALK4 antagonists having any type of molecular structure; a subgenus of such antagonists that are heteromultimers comprising ActRIIB and ALK4 polypeptides having any type of amino acid sequence; and further subgenera of such heteromultimers having ActRIIB and ALK4 polypeptides with defined amino acid sequences.
The instant specification provides extensive teachings regarding the amino acids that contribute to the ligand-binding domain of each protein (e.g., starting at ¶ 217 for ActRIIB, and starting at ¶ 294 for ALK4). Thus, with respect to the heteromultimers of the claims, the person of ordinary skill in the art would have recognized the teachings in the specification as being sufficient to provide written description for the genus of ActRIIB recited in dependent claim 302, and for the genus of ALK4 polypeptides recited in dependent claim 303. Specifically, an ActRIIB polypeptide comprising an amino acid sequence that is at least 90% identical to amino acids 25-131 of SEQ ID NO: 2, which is the extracellular domain of ActRIIB, or to SEQ ID NO: 2, which is the full-length sequence; and an ALK4 polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence of SEQ ID NO: 84, which is the extracellular domain of ALK4, or to SEQ ID NO: 86, which is the full-length sequence.
While the teachings of the specification are sufficient to provide written description for the indicated scope of ActRIIB and ALK4 polypeptide variants, the claims are not limited to such, and encompasses variants in which an unlimited number of changes are made to the reference sequences. The prior art appreciates that "Mutations … are generally destabilizing, and can reduce protein … fitness" and "In general, more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation" (pg 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). Thus, knowledge of the amino acid sequences of ActRIIB and ALK4 alone are not sufficient for the skilled artisan at the time of the effective filing date to predict which combinations of mutations (substitutions, additions and deletions) will result in functional a heteromultimer that is a functional antagonist corresponding in scope to the broad range of mutations encompassed by the claims.
With respect to the broader genus of ActRIIB-ALK4 antagonists that is defined by function alone (i.e., antagonism), a product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function; e.g., the structure of one of ActRIIB-ALK4 antagonist does not provide predictability regarding other structures having the same functionality. Furthermore, as the genus encompasses antibodies, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) is applicable; this held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g., ActRIIB or ALK4) is not in and of itself sufficient to provide a description of the genus of antibodies binding to said target.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
As noted above, the genus of ActRIIB-ALK4 antagonists encompasses inhibitors that have any structure; e.g., polypeptide, antibody, nucleic acid, small molecule, carbohydrate, lipid, inorganic molecule or other. Each of these types of molecules is a subgenus encompassing multiple structures. For example, ActRIIB-ALK4 antagonists that are antibodies include the entire range of monoclonal antibodies that bind to and inhibit ActRIIB or ALK4, as well as antibodies that indirectly inhibit the function of either protein, such as binding to a downstream signaling molecule. However, the specification does not provide examples of anti-ActRIIB or anti-ALK4 antibodies corresponding in scope to encompassed genus, and likewise does not provide examples of each of the other structural categories of antagonists (e.g., small molecules), which would be necessary to describe the entirety of the genus of antagonists. The working examples are limited to use of the aforementioned ActRIIB-ALK4 heteromultimer. Per MPEP 2163, "A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). As such, the description of structures of ActRIIB-ALK4 antagonists does not correspond that which is claimed, and therefore the specification fails to provide a written description of the genus of ActRIIB-ALK4 antagonists.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only a method 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 antagonist is a heteromultimer comprising an ActRIIB polypeptide that comprises an amino acid sequence that is at least 90% identical to amino acids 25-131 of SEQ ID NO: 2, and comprising an ALK4 polypeptide that comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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 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.
Claim Rejections - 35 USC § 102
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.
Claims 300-308 and 313-319 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kumar et al, U.S. Patent Application Publication 2018/0163187, published 6/14/18. The earliest date to which the instant application claims priority is 6/17/20.
Claims 300 and 301 each encompasses a method of treating heart failure (HF) in a patient in need thereof comprising administering an effective amount of an ActRIIB-ALK4 antagonist (claim 300), and further wherein the antagonist is a heteromultimer comprising an ActRIIB polypeptide and an ALK4 polypeptide (claim 301). Kumar teaches an “ALK4:ActIIRB heterodimer” that acts as antagonist (¶ 5). Kumar further teaches that “an ALK4:ActRIIB heteromultimer may be used to treat or prevent a disorder or condition selected from a group including … congestive heart failure” (¶ 228). Additional teachings with respect to the use of the heteromultimer in treatment of congestive heart failure are provided at ¶ 235, 252, and 268. As such, the teachings of Kumar anticipate claims 300 and 301.
Claim 302 encompasses a method of claim 301 wherein the ActRIIB polypeptide comprising an amino acid sequence that is at least 90% identical to an amino acid sequence of SEQ ID NO: 2. Kumar teaches that the ActRIIB polypeptide may have the sequence of SEQ ID NO: 1 (¶ 118), which is 100% identical to instant SEQ ID NO: 2. As such, the teachings of Kumar also anticipate claim 302.
Claim 303 encompasses a method of claim 301 wherein the ALK4 polypeptide comprises an amino acid sequence of SEQ ID NO: 84. Kumar teaches that the ALK4 polypeptide may have the sequence of SEQ ID NO: 10 (¶ 8), which is 100% identical to instant SEQ ID NO: 84. As such, the teachings of Kumar also anticipate claim 303.
Claims 304 and 306 encompass a method of claim 301, wherein the heteromultimer comprises a fusion polypeptide comprising an ActRIIB polypeptide domain and one or more heterologous domains and/or a fusion polypeptide comprising an ALK4 polypeptide domain and one or more heterologous domains (claim 304) and further wherein the one or more domains is an Fc domain (claim 306). Kumar further teaches that either the ALK4 or ActRIIB polypeptide may be a fusion protein with an Fc domain (¶ 13). As such, the teachings of Kumar also anticipate claims 304 and 306.
Claim 305 encompasses a method of claim 304, wherein one of the fusion polypeptides further comprises a linker between the polypeptide domain and the one or more heterologous domains, and wherein the linker selected from a group including GGG. Kumar further teaches linkers connecting the heterologous domains, including Fc domains, and teaches examples of linkers including GGG (¶ 32). As such, the teachings of Kumar also anticipate claim 305.
Claim 307 encompasses a method of claim 304, wherein the ALK4 fusion polypeptide comprising the amino acid sequence of SEQ ID NO: 92. Kumar further teaches an ALK4-Fc fusion protein having the sequence of SEQ ID NO: 47 (¶ 41), which is 100% identical to instant SEQ ID NO: 92. As such, the teachings of Kumar also anticipate claim 307.
Claim 308 encompasses a method of claim 304, wherein the ActRIIB fusion polypeptide comprising the amino acid sequence of SEQ ID NO: 402. Kumar further teaches an ActRIIB-Fc fusion protein having the sequence of SEQ ID NO: 45 (¶ 306), which is 100% identical to instant SEQ ID NO: 92. As such, the teachings of Kumar also anticipate claim 308.
Each of claims 313-317 limit the method of claim 300 by means of a “wherein” clause indicating a result of the claimed method. In each claim, the wherein clause has been fully considered in context of the entire claim, but does not render the claimed method patentably distinct from a method taught by the prior art because it simply expresses the intended result of a process step positively recited. See MPEP 2111.04, which states that a "whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited" (Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), quoting Minton v. Nat ’l Ass ’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). Specifically, in claims 313-317, the claims simply express an intended result (decreasing troponin levels or ventricular hypertrophy; or increasing LV diastolic function, ejection fraction, or cardiac output) of a process step positively recited (administering an ActRIIB-ALK4 antagonist). As such, the teachings of Kumar that anticipate parent claim 300 also meet the limitations of dependent claims 313-317.
Independent claim 318 encompasses a method of treating HF in a patient in need thereof comprising administering an effective amount of an ActRIIB-ALK4 heteromultimer comprising an ActRIIB fusion polypeptide comprising SEQ ID NO: 402 and an ALK4 fusion polypeptide comprising SEQ ID NO: 92. Kumar teaches all of the limitations of this claim as set forth above for claims 300, 301, 304, 307 and 308. As such, the teachings of Kumar also anticipate claim 318.
Independent claim 319 encompasses a method of treating one or more comorbidities of heart failure comprising administering to a patient in need thereof an effective amount of an ActRIIB-ALK4 agonist. Kumar further teaches use of the ALK4:ActRIIB heteromultimer for treatment of chronic kidney disease, and complication of kidney disease, which include congestive heart failure (¶ 252). As such, the teachings of Kumar also anticipate claim 319.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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.
Claims 309-312 are rejected under 35 U.S.C. 103(a) as being unpatentable over Kumar et al, U.S. Patent Application Publication 2018/0163187, published 6/14/18, as applied to claim 300 above, and further in view of Albakri et al, 2018. J Clin Invest Stud. 1(1): 1-13.
Claim 309 encompasses a method of claim 300 wherein the heart failure is selected from a group including dilated cardiomyopathy (DCM), which is the elected species under consideration. The teachings of Kumar that anticipate parent claim 300 are set forth above. While Kumar teaches treatment of congestive heart failure, Kumar does not teach treatment of heart failure that is DCM.
Albakri, in a review of DCM, teaches that “Congestive heart failure (CHF) due to poor cardiac function is a serious heart condition and the leading cause of morbidity and mortality in pediatric, adult and geriatric populations worldwide” (page 1). Albakri further teaches that DCM is one of the “main etiologies” of CHF (page 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the method of treatment of HF in a patient in need thereof comprising administering an ActRIIB-ALK4 antagonist that is a ActRIIB-ALK4 heteromultimer as taught by Kumar, and modify it to treat a patient with heart failure resulting from dilated cardiomyopathy (DCM). The person of ordinary skill in the art would have been motivated to make such a change in order to treat a subject having CHF resulting from DCM. In the absence of any evidence to the contrary, the person of ordinary skill in the art would reasonably expect a treatment taught for CHF in general, such as that of Kumar, to also be applicable to any type of CHF, particularly one linked to one of the main etiologies of CHF, such as CHF resulting from DCM. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Claims 310 and 312 encompass a method of claim 300 where in the patient has reduced LVEF and an LVEF of <40% (claim 310) or has reduced ejection fraction (claim 312). Albakri further teaches that DCM is characterized by an LVEF of less than 45% (page 5), and further describes patients with an LVEF of less than 25% and with symptoms of heart failure (page 6). As such, it would have further been obvious to take the method obvious over the teachings of Kumar in view of Albakri that meets the limitations of claim 309 and further modify to treat a DCM patient with reduced LVEF of less than 25% and having symptoms of heart failure as taught by Albakri. The person of ordinary skill in the art would have been motivated to make such a change in order to treat a subject having CHF resulting from DCM and an LVEF of less than 25%. In the absence of any evidence to the contrary, the person of ordinary skill in the art would reasonably expect a treatment taught by CHF in general to also be applicable to treatment of that subset of patients having CHF resulting from DCM and an LVEF of less than 25%.
Claim 311 encompasses a method of claim 300 wherein the patient has elevated levels of natriuretic peptides. Albakri further teaches that natriuretic peptides are “markers of DCM severity” (page 7). As such, it would have further been obvious to take the method obvious over the teachings of Kumar in view of Albakri that meets the limitations of claim 309 and further modify to treat a DCM patient having natriuretic peptides as a marker of DCM severity as taught by Albakri, which meets the limitation of having elevated natriuretic peptides. The person of ordinary skill in the art would have been motivated to make such a change in order to treat a subject having CHF resulting from DCM and having natriuretic peptides as a marker of DCM severity. In the absence of any evidence to the contrary, the person of ordinary skill in the art would reasonably expect a treatment taught by CHF in general to also be applicable to treatment of that subset of patients having CHF resulting from DCM and having natriuretic peptides as a marker of DCM severity.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674