DETAILED ACTION
Examiner acknowledges receipt of the reply filed 5/27/2025, in response to the restriction requirement mailed 04/03/2025.
Claims 1-4, 6, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 are pending. Claims 2 and 6 are withdrawn from further consideration for the reasons set forth herein.
Claims 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 are being examined on the merits in this office 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 .
Election/Restrictions
Applicant’s election of Group 1 (claims 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64) without traverse in the reply filed on 5/27/2025 is acknowledged.
Claims 2 and 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/27/2025.
Applicant’s election of the following species in the reply filed on 5/27/2025 is acknowledged. Election was made without traverse.
identity of ActRIIB (SEQ ID NO:46)
fully defined “interaction pair” (SEQ ID NOs: 14 and 15)
second polypeptide (SEQ ID NO:49)
linker present, SEQ ID NO:40
identity of additional therapeutic agent (derivatives of prostacyclin, e.g., treprostinil)
binding properties of the ActRIIB heteromultimer- intermediate strength binding to activin G, GDF11, GDF8 and/or activin A; weak or no binding to BMP10 and/to BMP9
Claims 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 read on the elected species.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc.
Claim Objections
Claims 1, 3, 20, 22, 23, 28, 29, 57, and 60 are objected to because of the following informalities:
Claims 1 and 3 should be amended to recite “a)[[.]] … b)[[.]]” . The claim should only have a period “.” at the end of the sentence.
The acronym ActRIIB should be written out in full name in the first order of appearance in the claims.
Claims 20, 28, 29 should be amended to recite amended to delete the “and/or” claim language. Further regarding claim 20, the acronym CHO should be written out in full name.
Regarding claims 22 and 23, the acronyms GDF11 and GDF8 should be written out in full name.
Regarding claim 29, all compounds should be recited in singular form, e.g. endothelial receptor antagonist arrow). All acronyms should be written out in full name in the first order of appearance. See at least ASK-1 at l. 8,CIIA at l. 9, NQDI-1 at ll. 9-10, CZVI4-2 at l. 24.
Claim 29 should be amended to recite compound names in lowercase- e.g., including but not limited to ll. 12-13:
3-acetyloleanolic acidtriflouroacetyloleanolic acid methylmethyl
Examiner requests that applicant thoroughly review all recited compounds in claim 29.
Claims 57 and 60 should be amended to recite the drug classes in singular form, e.g. phosphodiesterase type 5 inhibitor .
Appropriate correction is required.
USPTO Sequence Interpretation/Claim Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising an amino acid sequence of SEQ ID NO: 1” requires only a dipeptide or more within SEQ ID NO: 1, “comprising the amino acid sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with or without additional amino acids at any N-/C-terminal ends or additional nucleotides at 5' /3' ends, “consisting of an amino acid sequence of SEQ ID NO: 1” would encompass any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, and “consisting of the amino acid sequence of SEQ ID NO: 1” would be limited to the sequence of the amino acids as specified by SEQ ID NO: 1, and nothing more or less; "an amino acid selected from the group consisting of SEQ ID NOs: 1, 2 and 3” is any sequence of two or more consecutive amino acids (dipeptide or more) fully contained within SEQ ID NO: 1, 2 or 3; and “the amino acid selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3.
Claim Rejections - 35 USC § 112
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 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claim 1 is drawn to a method of treating pulmonary hypertension comprising administering a single-arm ActRIIB heteromultimer to a subject in need thereof, the heteromultimer comprising a first polypeptide covalently or non-covalently associated with a second polypeptide, wherein the first polypeptide comprises the amino acid sequence of a first member of an interaction pair and the amino acid sequence of ActRIIB polypeptide, and the second polypeptide comprises the amino acid sequence of a second member of the interaction pair, and wherein the second polypeptide does not comprise an amino acid sequence of ActRIIB. The claims do not require that the first member of an interacting pair, the second member of an interacting pair, and the ActRIIB polypeptide possess any particular biological activity, nor any particular conserved structure, nor other disclosed distinguishing feature. Claim 3 recites a partial structure for the ActRIIB polypeptide in the form of sequence similarity, whereas claims 14 and 15 recites a partial structure for the first polypeptide and the second polypeptide in the form of sequence similarity (at least 70% identical to a recited SEQ ID NO). Claims 3, 4, 7, 9, 13, 16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 depend from claim 1, either directly or indirectly.
The specification states that the term “ActRIIB polypeptide” includes polypeptides comprising any naturally occurring polypeptides of an ActRIIB family member as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a useful activity (page 22, 3rd paragraph). Thus, the claims are drawn to an enormous genus of the first polypeptides and the second polypeptides without any structural and functional features. The specification discloses a human ActRIIB precursor protein set forth in SEQ ID NO: 1, the mature extracellular ActRIIB polypeptide set forth in SEQ ID NO: 2 (pages 22-23), and the form of ActRIIB with an alanine at position 64 set forth in SEQ ID NOS: 4-5 (pages 23-24). The specification also discloses a single-arm ActRIIB-Fc heterodimer comprising a monomeric Fc polypeptide and the extracellular domain of human ActRIIB fused to a separate Fc (Example 1). However, such an instant disclosure does not adequately support the broad scope of the heteromultimer comprising a first polypeptide and a second polypeptide encompassed in the instant claims. Moreover, the specification does not disclose a heteromultimer comprising a first polypeptide non-covalently associated with a second polypeptide.
Vas-Cath Inc. v Mahurkar, 19 USPQ2d 1111 (Fed. Cir.1991), clearly states 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 purpose 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). Adequate written description requires more than a mere statement that it is part of the invention are reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir.1991).
An adequate written description of a chemical invention “requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir.2004); Regents of the Univ. of Cal. V. Eli Lilly & Co., Inc., 119 F.3d 1559, 1556 (Fed. Cir.1997); Fiers v. Revel, 984F.2d 1164, 1171 (Fed. Cir.1993). “A description of what a material does, rather than of what it is, usually does not suffice.” Rochester, 358F.3d at 923; Eli Lilly, 119 F.3d at 1568. In addition, possession of a genus “may be achieved by means of a recitation of a representative number of [compounds]…falling within the scope of the genus.” Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 f. 3d at 927.
Furthermore, the present application is attempting to patent what has not yet been invented and the fact that one of skill in the art can test for the effect used to determine the compounds does not necessarily confer sufficient written description. The claimed a single-arm ActRIIB heteromultimer sequence would entail testing limitless potential by peptides, and one of skill in the art could afterwards still be faced with no hits with the desired functionality.
In addition, it is well known in the peptide/protein art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein’s function. As an example of the unpredictable effects of mutations on protein function, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section “CYSTIC FIBROSIS”. Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation ΔF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2nd paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. Although the disclosures of Drumm et al and Yampolsky et al are directed to proteins/peptides other than the claimed a single-arm ActRIIB heteromultimers, they illustrate the inherent unpredictability with respect to the biological activity of a given protein/peptide after even minor changes to the primary amino acid sequence.
Therefore, based on the state of art, a person of ordinary skilled in the art would not be able to determine what structural feature is required for the claimed single-arm ActRIIB heteromultimers.
In the instant case, the genus of instant claimed peptide sequences recited encompasses numerous variants which may include any number of natural and unnatural amino acids. Elected ActRIIB of SEQ ID NO: 46 is 368 amino acids in length. A sequence of 70% identity allows for 110 amino acid changes. If one considers that 110 amino acids can be changed (70% identity) to 20 different naturally occurring amino acids this is 11020 or 6.73 x1040. The elected second polypeptide of SEQ ID NO:49 is 262 amino acids in length. A sequence of 70% identity allows for 78 amino acid changes. If one considers that 78 amino acids can be changed (70% identity) to 20 different naturally occurring amino acids this is 7820 or 6.95 x1037. These numbers are actually significantly higher when one considers both naturally and unnaturally occurring amino acids. It is further noted that these numbers do not take into consideration the sequence of the first number of an interaction pair, much less combinations of the ActRIIB polypeptide, first number of an interaction pair, and the second polypeptide
Considering the scope of the genus of instant claimed single-arm ActRIIB heteromultimer sequence, the instant specification fails to provide sufficient examples to describe the entire genus of single-arm ActRIIB heteromultimers claimed.
Taken all these together, considering the state of the art and the disclosure in instant specification, it is deemed that the instant specification fails to provide adequate written description for the claimed genus of the first polypeptides, the second polypeptides, and single-arm ActRIIB heteromultimers, and lack of the definitive structural and functional features of the genus, one skilled in the art would not recognize from the disclosure that Applicant was in possession of the genus of the single-arm ActRIIB heteromultimers and thus the method of using the same.
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 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 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 1 recites “a first member of an interaction pair” and “a second member of the interaction pair”. It is unclear what the metes and bounds of the limitations are.
Claim 1 recites a term “single-arm heteromultimer”. Since neither the specification nor the prior art defines the term unambiguously, the claim is indefinite.
Claim 1 further recites “non-covalently associated with …”. The specification does not provide a definition for it. One of skill in the art would not know how a first polypeptide is “non-covalently associated” with a second polypeptide.
Claims 3, 4, 6, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 are rejected as dependent claims from claim 1.
Claim clarification is required
The metes and bounds of claims 20 and 29 respectively are deemed to be indefinite. The claims each recite multiple “and/or” alternatives thus it is unclear as to what the criteria for inclusion or exclusion of the claim terms.
Further regarding claim 29, claim recites “wherein the additional active agent and/or supportive therapy for treating pulmonary hypertension is selected from the group consisting of … lung and/or heart transplantation. Claim 29 recites class of drugs and then recites “lung and/or heart transplantation”. These are medical procedures, not drugs much less categories of works. It is unclear what applicant intends by the phrase “lung and/or heart transplantation”.
Regarding claim 29, the use of parenthetical phrases render the claims indefinite because it is unclear whether the limitations following the phrases or in parentheses are part of the claimed invention. Claim 29 further recites “e.g.” multiple times in claim rendering the claim indefinite. See MPEP § 2173.05(d).
Examiner recommends that applicant deletes the parenthetical limitations from claim 29 and includes in a new dependent claim for each of the claimed drug classes. For instance, new claim 67:
67. (New) the method of claim 29, wherein the prostacyclin or derivative thereof is selected from the group consisting of epoprostenol, treprostinil, and iloprost.
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 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kumar et al (U.S. 2018/0050089).
Kumar et al teach GDF/BMP antagonists and methods of using GDF/BMP antagonists to treat, prevent, or reduce the progression rate and/or severity of pulmonary hypertension (PH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PH-associated complications (abstract). Kumar et al teach an ALK4:ActRIIB heterodimer can be used to treat PH (e.g., para. [0006]-[0010], [0170]-[0183]; Examples 4, 12-15, Figs 23 A-D). The ActRIIB polypeptide fused to a Fc domain. Accordingly, a first polypeptide comprises an ActRIIB polypeptide and a first member of an interaction pair (Fc domain, e.g. C1), the second polypeptide comprises a second member of an interaction pair (2nd Fc domain, e.g. C2). Examiner notes that the instant specification does not expressly define the term “single-arm”. Kumar et al reduced to practice a ALK4:ActRIIB heteromultimer (can be a heterodimer) wherein only one of the polypeptides comprises ActRIIB. Accordingly, instant claims 1 and 7 are satisfied.
Regarding claim 3, SEQ ID NO:1 of Kumar et al has 100% identity with instant SEQ ID NO:1. Regarding claim 4, the ActRIIB polypeptide is not comprise an acidic amino acid that section L79 of SEQ ID NO:1 (para. [0010]-[0011], [0120]). Regarding claim 9, the interaction pair comprises a constant region from an IgG heavy chain (e.g., paras. [0014], [0065], [0152]-[0165], [0180]). Regarding claim 13, Kumar et al teach IgG heavy chains with identity to the claimed SEQ ID NOs (e.g., paras [0014], SEQ ID NOs:23-37). Regarding claim 14, Kumar et al teach SEQ ID NO:108 which has 100% identity with instant SEQ ID NO: 46. Regarding claim 15, Kumar et al teach SEQ ID NO:111 which has 93.4 % identity with instant SEQ ID NO: 49. Regarding claims 16 and 18, Kumar et al teach that a linker may be positioned between the ActRIIB polypeptide and Fc domain (paras. [0031]-[0032], [0065]). Linkers include GGG (SEQ ID NO: 13), GGGG (SEQ ID NO: 14), TGGGG (SEQ ID NO: 15), SGGGG (SEQ ID NO: 16), TGGG (SEQ ID NO: 17), SGGG (SEQ ID NO: 18), or GGGGS (SEQ ID NO: 58) singlets, or repeats (para. [0177]). Regarding claim 20, the reference teaches that the polypeptide can be glycosylated from expression in a CHO cell (e.g., paras. [0007], [0031], [0191]-[0192]). Regarding claims 22 and 23, Kumar et al teach that the heterodimers bind to activin A, activin B, GDF8, and GDF11 (e.g., paras. [0006]-[0008], claims 152 and 153; Examples 6-10, 13). Regarding claim 27, the pulmonary hypertension includes pulmonary arterial hypertension (e.g., paras. [0006]-[0008], [0277]-[0284], Ex 14). Regarding claims 28, 29, and 60, the subject may be administered in additional active agent such as treprostinil (e.g., para. [0009]). Regarding claim 30, the subject has a resting PAP of at least 25 mm Hg (e.g., para. [0286]). Regarding claim 32, the method reduces the PAP by at least 3 mm Hg (e.g., para. [0008], [0287]). Regarding claim 38, the method increases the subjects 6 minute walk distance by at least 10 m (e.g., para. [0007]-[0008], [0289]). Regarding claim 41, the subject has Functional Class II or Class III pulmonary hypertension according to the WHO classification system (e.g., para. [0007], [0290], claims 89-91). Regarding claim 47, the method decreases ventricle hypertrophy by at least 10% (e.g., para [0007], Examples 14-15). Regarding claim 57, subjects include those previously treated with a vasodilator, phosphodiesterase type 5 inhibitor, soluble guanylate cyclase stimulator, prostacyclin receptor agonist, or endothelin receptor antagonist (para. [0007]). Regarding claim 64, the method delays clinical worsening of pulmonary hypertension (e.g., para. [0007], [0008]).
Claims 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kumar et al (U.S. 20180163187- hereinafter referred to as “the ‘187 reference”).
The ‘187 reference teaches ALK4:ActRIIB heteromultimers wherein the heteromultimers comprise ALK4-Fc and ActRIIB-Fc fusion proteins wherein the Fc domains of the respective ALK4- and ActRIIB- fusion proteins form an interaction pair (claim 1, paras. [0009]-[0030], [0057]-[0058], [0094]-[0097], [0152]-[0153], Examples 1-3, Figs 6 A-D). The ActRIIB polypeptide is fused to a Fc domain. Accordingly, a first polypeptide comprises an ActRIIB polypeptide and a first member of an interaction pair (Fc domain, e.g. C1), the second polypeptide comprises a second member of an interaction pair (2nd Fc domain, e.g. C2). Examiner notes that the instant specification does not expressly define the term “single-arm”. The ‘187 reference reduced to practice a ALK4:ActRIIB heteromultimer (can be a heterodimer) wherein only one of the polypeptides comprises ActRIIB. The ‘187 reference teaches that the heteromultimers can be administered to a subject to treat pulmonary hypertension, including pulmonary arterial hypertension (e.g., para. [0057]-[0058], [0260]-[0270]). Accordingly, instant claims 1 and 7 are satisfied.
Regarding claim 3, SEQ ID NO:1 of the ‘187 reference has 100% identity with instant SEQ ID NO:1. Regarding claim 4, the ActRIIB polypeptide is not comprise an acidic amino acid that section L79 of SEQ ID NO:1 (para. [0010]-[0011], [0120]). Regarding claim 9, the interaction pair comprises a constant region from an IgG heavy chain (e.g., paras. [0014], [0065], [0150]-[0165], Ex 1). Regarding claim 13, the ‘187 reference teaches IgG heavy chains with identity to the claimed SEQ ID NOs (e.g., paras [0014], SEQ ID NOs:23-37). Regarding claim 14, the ‘187 reference teaches SEQ ID NO:39 which has 100% identity with instant SEQ ID NO: 46. Regarding claim 15, the ‘187 reference teaches SEQ ID NO:42 which has 93.4% identity with instant SEQ ID NO: 49. Regarding claims 16 and 18, the ‘187 reference teaches that a linker may be positioned between the ActRIIB polypeptide and Fc domain (paras. [0031]-[0032], [0065]). Linkers include GGG (SEQ ID NO: 13), GGGG (SEQ ID NO: 14), TGGGG (SEQ ID NO: 15), SGGGG (SEQ ID NO: 16), TGGG (SEQ ID NO: 17), SGGG (SEQ ID NO: 18), or GGGGS (SEQ ID NO: 58) singlets, or repeats (para. [0179]). Regarding claim 20, the reference teaches that the polypeptide can be glycosylated from expression in a CHO cell (e.g., paras. [0044], [0051]-[0053], [0194]-[0195]). Regarding claims 22 and 23, the heteromultimers bind to activin A, activin B, GDF8, and GDF11 (e.g., paras. [0005]-[0006], [0045]-[0046], claims 159; Example 2). Regarding claim 27, the pulmonary hypertension includes pulmonary arterial hypertension (e.g., paras. [0057]-[0058], [0260]-[0262]). Regarding claims 28, 29, and 60, the subject may be administered in additional active agent such as treprostinil (e.g., para. [0057]-[0058]). Regarding claim 30, the subject has a resting PAP of at least 25 mm Hg (e.g., para. [0058], [0264]). Regarding claim 32, the method reduces the PAP by at least 3 mm Hg (e.g., para. [0058], [0265]). Regarding claim 38, the method increases the subjects 6 minute walk distance by at least 10 m (e.g., para. [0057]-[0058], [0267]). Regarding claim 41, the subject has Functional Class II or Class III pulmonary hypertension according to the WHO classification system (e.g., para. [00057], [0268]-[0269]). Regarding claim 47, the method decreases ventricle hypertrophy by at least 10% (e.g., para [0057]-[0058], [0265]-[0266]). Regarding claim 57, subjects include those previously treated with a vasodilator, phosphodiesterase type 5 inhibitor, soluble guanylate cyclase stimulator, prostacyclin receptor agonist, or endothelin receptor antagonist (para. [0057]). Regarding claim 64, the method delays clinical worsening of pulmonary hypertension (e.g., para. [0057], [0058]).
Relevant Art Not Relied Upon
Kumar et al (U.S. 2016/0289298- hereinafter referred to as “the ‘298 reference”) teach single-arm ActRIIB-Fc:Fc constructs and ligand binding characteristics. Example 1 discloses a single-arm ActRIIB-Fc heterodimer comprising and a first polypeptide in which the extracellular domain of ActRIIB is fused to a separate Fc domain with a linker position between the extracellular domain and the Fc domain, and a second polypeptide comprising monomeric Fc polypeptide with a short N-terminal extension. The ‘298 reference further discloses methods for promoting formation of ActRIIB-Fc:Fc heterodimeric complexes by altering the amino acid sequence of the Fc domains for formation of asymmetric complexes. The single-arm ActRIIB-Fc has greater ligand selectivity than the homodimeric ActRIIB-Fc. Whereas the ActRIIB-Fc homodimer bind strongly to each of the activin A/B, BMP10, GDF8, and GDF1; single-arm ActRIIB-Fc bind strongly to activin B and GDFf11, with intermediate strength to GDF8 and activin A. Single-arm ActRIIB-Fc displays only weak binding to BMP10 and no binding to BMP9, in contrast to homodimeric ActRIIB-Fc. See Example 1.
The ‘298 reference does not explicitly or implicitly teach or suggest a method of treating pulmonary hypertension.
Conclusion
No claims are allowed.
Claims 1-4, 6, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 are pending. Claims 2 and 6 are withdrawn.
Claims 1, 3, 4, 7, 9, 13-16, 18, 20, 22, 23, 27-30, 32, 38, 41, 47, 57, 60, and 64 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654