DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/03/2026 has been entered. Claims 1, 4, 7, 20 and 24-26 are amended, claim 23 is newly canceled and claims 28-31 are new.
Claims 1, 4, 7, 11, 20-22 and 24-31 are under examination.
Election/Restrictions
In the Requirement for Restriction mailed 04/11/2023, the examiner stated independent claims 1 and 12 were generic to the patentably distinct species listed at Table 1, paragraph [0035] of the instant specification (see p. 5 under “PART B”). In the Response to Election filed 06/05/2023, Applicant did not choose a single species, but rather elected “FSH lowering agents”, thereby encompassing all of the species listed in Table 1. The examiner did not raise an issue with the election; thus, all of the species are under examination. Applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Effective Filing Date
A new matter rejection over the claims is made below, thus the effective filing date of the claims filed 03/03/2026 is 03/03/2026. Entitlement to a filing date does not extend to subject matter which is not disclosed, but would be obvious over what is expressly disclosed. See Lockwood v. American Airlines Inc., 41 USPQ2d 1961 (Fed. Cir. 1977).
Claim Interpretation
In claim 4, there is implicit support for a bolus ovulatory trigger dose of one or more of: LH, an LH derivative, hCG, an hCG derivative and/or a gonadotropin releasing hormone agonist, at paragraph [0017] of the instant specification, which states that these “adjunct medications” may be also administered to trigger ovulation. While there is no explicit support for the “ovulatory trigger dose is administered in each cycle of patient treatment in order to induce oocyte maturation and ovulation in said cycle” in claim 4, paragraphs [0023] and [0024] of the instant specification disclose the agents of the invention are administered for two or more cycles. This disclosure along with paragraph [0017] provides implicit support for “a bolus ovulatory trigger dose of one or more of: LH, an LH derivative, hCG, an hCG derivative and/or a gonadotropin releasing hormone agonist, wherein said ovulatory trigger dose is administered in each cycle of patient treatment in order to induce oocyte maturation and ovulation in said cycle”.
Rejections Withdrawn
Note, any previous rejections over claim 23 are hereby withdrawn in response to Applicant’s cancelation of that claim.
Claim Rejections - 35 USC § 102
The rejection of claim 4 under 35 U.S.C. 102(a)(1) as being anticipated by Menezo (WO 03/022303—on IDS filed 10/05/2021) is withdrawn in response to Applicant’s amendment of claim 4 to delete LH and hCG as possible FSH lowering agents. Menezo et al. teach administering hCG and/or LH to a human female for a portion of the reproductive cycle (see claims 1, 16 and 23), but they do not teach the other FSH lowering agents recited in amended claim 4.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 4, 7, 11, 20-22 and 24-27 under 35 U.S.C. 103 as being unpatentable over Bernstein et al. (WO 2008140794—on IDS filed 10/05/2021) in view of Ruckle et al. (J Bone Miner Res 2009; 24: 744-752) is withdrawn in response to Applicant’s amendment of the independent claims to recite FSH is not administered to the female subject. Bernstein et al. suggest administering FSH at different doses throughout the menstrual cycle to achieve levels in young and healthy females (see, e.g., p. 8, lines 16-18).
The rejection of claims 1, 7 and 11 under 35 U.S.C. 103 as being unpatentable over Menezo (WO 03/022303—on IDS filed 10/05/2021) in view of Katz-Jaffe et al. (Obstet Gynecol 2013; 121: 71-7) is withdrawn in response to Applicant’s amendment of the independent claims to recite FSH is not administered to the female subject. Menezo suggests administering FSH as part of controlled ovarian hyperstimulation (see, e.g., claim 1).
New Objections/Rejections
Claim Objections
Claims 24, 25 and 31 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim must refer back in the alternative only. See MPEP § 608.01(n). Accordingly, the claims 24 and 25 have not been further treated on the merits. In addition, new claim 31, which depends from claim 24, is also not being further treated on the merits.
Claim 1 has been amended to recite that the FSH lowering agent “can lower FSH ligand”, which is redundant, since FSH itself is the ligand for the FSH receptor. See Figures 1 and 2 of the instant application, which show that FSH levels and concentrations are decreased after administration of ActRIIB:Fc. It is suggested the phrase be amended to recite simply “can lower FSH” or “can lower FSH levels”.
Claims 1, 4, 20 and 26 are objected to because of the following informalities. Claims 1, 4, 20 and 26 use the acronym “AKA”, in the context of defining other acronyms. So, for instance, claim 1 recites “AKA 3HP”, “AKA 3αHPA”, “AKA AMH” and “AKA APM”. Given the context of “AKA” in claims 1, 4, 20 and 26, it is interpreted as “also known as”. Nevertheless, using an undefined acronym to define other acronyms is grammatically awkward. It is suggested acronyms be defined by writing them parenthetically after the full name is written out, as is the custom in claim language. For instance, “3α hydroxy-4-pregnene-20-one (3αHP)”.
In addition, claims 1, 4, 20 and 26 recite “TGF13”, but presumably “TGFβ” was intended. It is noted that this is also misspelled in the specification (see p. 8, Table 1, paragraph [0035]).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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, 4, 7, 11, 20-22 and 26-30 are 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.
Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. Claims 1, 4, 20 and 26 recite:
including splice variants 288 and 315;
including aa90-95; aa81-95; and/or aa 35-53;
including aa551-555; 533-555; 650-653;649-653;
including but not limited to PRDC, gremlin, chordin, and/or noggin; follistatin;
including splice variants 288 and 315;
including anti activin receptor antibodies and derivative agents;
including but not limited to camelids and adnectins directed to bind and antagonize Activin A, B, or activin AB;
including but not limited to SB431542, LY-2157299; and
follistatin derivatives with or without fusion Fc regions, domain modifications or deletions.
In the context of the claims, the phrases “including” and “with or without” read upon exemplary language. It is unclear whether the limitations following “including” or “with our without” are part of the claimed invention or are intended as illustrations. See MPEP § 2173.05(d).
Claims 1, 4, 20 and 26 are also unclear because the list of FSH lowering agents and activin pathway modifying agents are chosen from a Markush grouping, which is a closed group of alternatives (see MPEP 2173.05(h), citing Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. The MPEP 2173.05(h) also provides guidance as to the proper language for reciting alternatives, which may be set forth as “a material selected from the group consisting of A, B, and C” or “wherein the material is A, B, or C”. Since the claim employs language similar to “wherein the material is A, B, or C”, the proper conjunction is “or”, not “and/or” as is currently recited in the independent claims.
Claims 1, 4, 20 and 26 contain the trademark/trade name “Adnectin”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to describe “therapeutic proteins based on the 10th fibronectin type III domain” that “share with antibody variable domains a beta-sheet sandwich fold with diversified loops, but…have a simpler, single-domain structure without disulfide bonds” (see abstract of D. Lipovšek, Protein Engineering, Design & Selection vol. 24 no. 1–2 pp. 3–9, 2011) and accordingly, the description is indefinite.
Claims 1, 4, 20 and 26 also recite the following functional language for defining activin pathway modifying agents: (a) “Nodal agents with reduced signaling capacity but that still bind receptors” and (b) “antibodies or other engineered agents including but not limited to camelids and adnectins directed to bind and antagonize Activin A, B, or activin AB”. When examining claims that contain functional language to determine whether the language is ambiguous, examiners should consider the following non-limiting factors: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim (see MPEP 2173.05(g)).
Nodal agents are described at the website: https://synapse.patsnap.com/article/ what-are-nodal-modulators-and-how-do-they-work:
NODAL modulators represent a fascinating area of biomedical research with significant implications for both science and medicine. These compounds are intricately involved in the regulation of embryonic development, cellular differentiation, and tissue regeneration. NODAL itself is a member of the TGF-β (Transforming Growth Factor-beta) superfamily, a group of proteins known for their roles in cellular processes and signaling pathways. Understanding the function and potential applications of NODAL modulators opens up new avenues for therapeutic interventions in various diseases and developmental disorders.
How do NODAL modulators work?
NODAL signaling is a complex and tightly regulated process that involves the interaction of NODAL proteins with specific receptors on the cell surface. These receptors, known as Activin receptors, initiate a cascade of intracellular events once they bind to NODAL. The primary mechanism through which NODAL modulators exert their influence is by either enhancing or inhibiting these signaling pathways.
The term “nodal agents” can also be used to describe a diverse category of drugs that slow or block conduction though the atrioventricular node to control heart rate and treat arrhythmias. Given the context of the claimed methods, it is likely that the recited “Nodal agents” interact with activin receptors, nevertheless, the term is vague. Further, the description at the website notes that NODAL modulators may either enhance or inhibit signaling pathways, and given that the claim recites “Nodal agents with reduced signaling capacity but that still bind receptors”, this remains unclear. In summary, with regard to the recited Nodal agents, there is no clear-cut indication of the scope of the subject matter covered by the claim, the language does not set forth well-defined boundaries of the agent and one of ordinary skill in the art would not know from the claim terms what structure is encompassed by the claim
As noted above, Adnectinstm are a trade name that describe single-domain antibody like structure without disulfide bonds. In the instant case, these structures have the function of binding and antagonizing activin A, activin B or activin AB. Lipovšek defines the process of Adnectintm discovery (p. 7, left column, last 2 paragraphs, citations omitted by examiner):
The steps that lead from human 10Fn3 to therapeutic Adnectins include:
(i) design and construction of 10Fn3-based libraries;
(ii) selection of target-binding molecules from the library using in vitro display;
(iii) screening of selected sequences for predicted immunogenicity;
(iv) screening of individual selected, bacterially produced proteins for favorable biophysical properties, including detailed binding kinetics, epitope-mapping, stability and solubility;
(v) screening of the proteins for in vitro activity in cell-based assays;
(vi) optimization of selected Adnectins by focused re-diversification and re-selection;
(vii) modification for improved pharmacokinetics;
(viii) characterization of biological efficacy in animal models; [and]
(ix) clinical trials in human patients.
In addition, detailed structural characterization of Adnectin-target complexes using X-ray crystallography continues to inform the discovery process, especially library design and optimization strategies.
In summary, with regard to the recited Adnectinstm, there is no clear-cut indication of the scope of the subject matter covered by the claim, the language does not set forth well-defined boundaries of the agent and one of ordinary skill in the art would not know from the claim terms what structure is encompassed by the claim.
Claims 7, 11, 21, 22 and 27-30 are hereby included in this rejection for depending upon indefinite claims without resolving the indefiniteness.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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, 4, 7, 11, 20-22 and 26-30 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 claims contain 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. This is a new matter rejection. Regarding claims 1, 4, 20 and 26, there is no explicit, implicit or inherent support for the newly added limitation of “wherein FSH is not administered to the female subject”. In addition, in claim 1, there is no explicit, implicit or inherent support for the amendment reciting that the FSH lowering agent “can lower…FSH activity”.
Regarding the first limitation, the specification explicitly discloses that when administering gonadotropin releasing hormone antagonists, low dose LH or hCG can be co-administered, “but no FSH is needed…because [GnRH antagonists] partially lower FSH while strongly suppressing LH” and “will normalize FSH through the cycles of treatment” (see paragraph [0027]). Thus, in the narrow embodiment of administering GnRH antagonists, the specification suggests FSH is not necessary, but this phrase does not broadly suggest that FSH is excluded from all of the other embodiments. Indeed, the specification discloses that the activin pathway modifying agents may be used in conjunction with assisted reproductive technologies such as IVF (see paragraph [0022]), which typically require administering FSH as part of the protocol (see p. 1, lines 1-20 of Menezo—of record). Further, the instant application does not provide any explicit, implicit or inherent support for lowering FSH activity. One of the few explicit mentions of activity in the instant specification discloses that “[t]he basis for therapeutic activity of APM [activin pathway modifying] agents is not necessarily based on FSH-lowering properties”, which does not provide any support for FSH-lowering activity. Rather, the instant application suggests that ActRIIB:Fc lowers FSH levels (see Figures 1 and 2), but is silent with regard to activity.
The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112 (see Eli Lilly, 119 F.3d at 1567, 43 USPQ2d at 1405). In other words, “[e]ntitlement to a filing date does not extend to subject matter which is not disclosed, but would be obvious over what is expressly disclosed.” See MPEP 2163.02, which cites Lockwood v. American Airlines Inc., 41 USPQ2d 1961 (Fed. Cir. 1977).
Lockwood argues that the district court erred by looking solely at the applications themselves. We do not agree. It is the disclosures of the applications that count. Entitlement to a filing date does not extend to subject matter which is not disclosed, but would be obvious over what is expressly disclosed. It extends only to that which is disclosed. While the meaning of terms, phrases, or diagrams in a disclosure is to be explained or interpreted from the vantage point of one skilled in the art, all the limitations must appear in the specification. The question is not whether a claimed invention is an obvious variant of that which is disclosed in the specification. Rather, a prior application itself must describe an invention, and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date
sought. See Martin v. Mayer, 823 F.2d 500, 504, 3 USPQ2d 1333, 1337 (Fed.Cir. 1987) (stating that it is “not a question of whether one skilled in the art might be able to construct the patentee's device from the teachings of the disclosure…Rather, it is a question whether the application necessarily discloses that particular device.”) (quoting Jepson v. Coleman, 314 F.2d 533, 536, 136 USPQ 647, 649-50 (CCPA 1963)). Lockwood argues that all that is necessary to satisfy the description requirement is to show that one is “in possession” of the invention. Lockwood accurately states the test, see Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed.Cir. 1991), but fails to state how it is satisfied. One shows that one is “in possession” of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious. Id. (“[T]he applicant must also convey 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.”) (emphasis in original). One does that by such descriptive means as words, structures, figures, diagrams, formulas, etc., that fully set forth the claimed invention. Although the exact terms need not be used in haec verba, see Eiselstein v. Frank, 52 F.3d 1035, 1038, 34 USPQ2d 1467, 1470 (Fed.Cir. 1995) (“[T]he prior application need not describe the claimed subject matter in exactly the same terms as used in
the claims...”), the specification must contain an equivalent description of the claimed subject matter. A description which renders obvious the invention for which an earlier filing date is sought is not sufficient.
While it may be obvious to forgo administering FSH or that an FSH lowering agent lowers FSH activity, the application as originally filed does not provide support for the amended claims. Applicant is encouraged to specifically point out the support for any amendments made to the claims.
Claims 1, 4, 7, 11, 20-22 and 26-30 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 claims contain 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. This is a written description rejection.
The claims are drawn to methods of treating/reducing infertility, miscarriages, trisomic pregnancies, birth defects, increasing oocyte production and/or yield of healthy oocytes to be ovulated comprising administering an FSH lowering agent and/or an activin pathway modifying (APM) agent selected from the lists recited in the claims. Some of the recited APM agents are recited in terms of their function rather than their structure, namely: (a) Nodal agents with reduced signaling capacity but that still bind receptors; (b) antibodies or other engineered agents such as camelids and adnectins directed to bind and antagonize Activin A, B, or activin AB; (c) dominant negative activins and decoy ligands of activin A, activin B, myostatin and GDF11; (d) TGFβ antagonists with altered ligand specificities toward activin ligands; and (e) peptides and related agents with dominant negative effect on activin receptor signaling.
The MPEP 2163(A) states “‘[a]n invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.’” For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. (See MPEP 2163(II)(A)(3)(a)(i)). To provide 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
Nodal agents are defined in the instant specification with the same functional language as recited in the claims at p. 9, Table 1, however, no examples of such agents are disclosed. Nodal agents are described at the website: https://synapse.patsnap.com/ article/what-are-nodal-modulators-and-how-do-they-work:
NODAL modulators represent a fascinating area of biomedical research with significant implications for both science and medicine. These compounds are intricately involved in the regulation of embryonic development, cellular differentiation, and tissue regeneration. NODAL itself is a member of the TGF-β (Transforming Growth Factor-beta) superfamily, a group of proteins known for their roles in cellular processes and signaling pathways. Understanding the function and potential applications of NODAL modulators opens up new avenues for therapeutic interventions in various diseases and developmental disorders.
How do NODAL modulators work?
NODAL signaling is a complex and tightly regulated process that involves the interaction of NODAL proteins with specific receptors on the cell surface. These receptors, known as Activin receptors, initiate a cascade of intracellular events once they bind to NODAL. The primary mechanism through which NODAL modulators exert their influence is by either enhancing or inhibiting these signaling pathways.
Thus, the art does not provide sufficient description of the structure of Nodal agents. Similarly, the specification provides no disclosure of dominant negative activins and decoy ligands of activin A, activin B, myostatin and GDF11, TGFβ antagonists with altered ligand specificities toward activin ligands; and peptides and related agents with dominant negative effect on activin receptor signaling. The claims encompass a vast genus of peptides, proteins and small molecules, however, the application does not provide a representative number of species to adequately describe this genus. In summary, the recited functional characteristics are not coupled with a known or disclosed correlation between the function and the structure of the encompassed molecules.
Antibodies, camelids and adnectins are recited in terms of their ability to bind and antagonize activins. The structure of antibodies is generally known. Antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Townsend et al. (Frontiers in Immunology, 7, 388 2016) teach “[v]ariability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing”, with the “most diverse” regions being the 6 CDR regions in the heavy and light chain. While the heavy chain is the most diverse, light chains are also important for binding specificity of antibodies, swapping light chains can “change the antigen specificity of the antibody” (see paragraph bridging pages 1-2). Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combinations of heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia et al. (Biochem. Engin. J. 137, 365-374, 2018), which teaches that “the maximal chemical diversity of antibody CDRs is unimaginably large…[and] it is extremely challenging to define the sequence determinant of antibody specificity” (see p. 368 left column, 4th paragraph). Regarding Adnectinstm, these describe single-domain antibody like structures without disulfide bonds. While the 10Fn3 structure may be generally known, the reference by Lipovšek (cited above) suggests a long process for designing and generating Adnectinstm, however, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. In summary, there is no identification of the structure of the agents that capable of the recited functions and the art demonstrates that antibody structure can vary widely and knowledge of antigen is not sufficient to describe the antibody.
The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), in which it was explained in that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Further, citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the Federal Circuit also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). Adequate written description requires more than a mere statement that it is part of the invention and 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.
The instant claims recite the agents as defined by their functions:
Nodal agents with reduced signaling capacity but that still bind receptors;
antibodies, camelids and adnectins directed to bind and antagonize Activin A, B, or activin AB;
dominant negative activins and decoy ligands of activin A, activin B, myostatin and GDF11;
TGFβ antagonists with altered ligand specificities toward activin ligands; and
peptides and related agents with dominant negative effect on activin receptor signaling)
In the instant case, the recitation of function alone in the claims is little more than a wish for possession and does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing “a result that one might achieve if one made that invention”); In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does “little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate”). Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, 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 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). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claims 1, 4, 7, 11, 20-22 and 26-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administering ActRIIA-Fc or anti-Müllerian hormone (AMH) to treat or reduce the incidence of infertility, miscarriages, trisomic pregnancies or birth defects, does not reasonably provide enablement for the claims as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The claims are broad with respect to the recited FSH lowering agents that can lower FSH ligand and/or FSH activity and activin pathway modifying (APM) agents. The claims require treatment of infertility and its related sequalae (miscarriages, trisomic pregnancies and birth defects resulting from aneuploidy) comprising administering FSH lowering and/or APM agents. These agents include:
Derivatives of Inhibin A, Inhibin B, myostatin, follistatin and anti-activin receptor antibodies;
TGFβ antagonists with altered ligand specificities toward activin ligands;
Activin receptor-binding activin peptides and related agents with dominant negative effect on activin receptor signaling;
Antibodies and other engineered agents such as camelids and adnectins directed to bind and antagonize Activin A, B, or activin AB;
Dominant negative activins and decoy ligands of activin A, activin B, myostatin and GDF11;
Nodal agents with reduced signaling capacity but that still bind receptors; and
RNA interference towards FSH, FSH receptor alpha and/or beta expression; ActRIIA, ActRIIB, Alk4, Smad2, Smad3, Activin A and/or Activin B.
Regarding the derivatives of Inhibin A, Inhibin B, myostatin, follistatin, anti-activin receptor antibodies, TGFβ antagonists with altered ligand specificities toward activin ligands; agents related to activin receptor-binding activin peptides with dominant negative effect on activin receptor signaling; antibodies, other engineered agents such as camelids and adnectins directed to bind and antagonize Activin A, B, or activin AB; dominant negative activins and decoy ligands of activin A, activin B, myostatin and GDF11 and Nodal agents with reduced signaling capacity but that still bind receptors, these encompass a large number of agents defined by their function, but with few structural limitations. Some structures such as antibodies, peptides and polypeptides are broadly known, however, the specification does not provide any examples of the encompassed derivatives of this laundry list of antibodies, peptides and polypeptides. Further, the claims encompass not just proteins and antibodies but small molecules.
For instance, Nodal agents are defined in the instant specification with the same functional language as recited in the claims at p. 9, Table 1, however, no examples of such agents are disclosed. Nodal agents are described at the website: https://synapse.patsnap.com/ article/what-are-nodal-modulators-and-how-do-they-work:
NODAL modulators represent a fascinating area of biomedical research with significant implications for both science and medicine. These compounds are intricately involved in the regulation of embryonic development, cellular differentiation, and tissue regeneration. NODAL itself is a member of the TGF-β (Transforming Growth Factor-beta) superfamily, a group of proteins known for their roles in cellular processes and signaling pathways. Understanding the function and potential applications of NODAL modulators opens up new avenues for therapeutic interventions in various diseases and developmental disorders.
How do NODAL modulators work?
NODAL signaling is a complex and tightly regulated process that involves the interaction of NODAL proteins with specific receptors on the cell surface. These receptors, known as Activin receptors, initiate a cascade of intracellular events once they bind to NODAL. The primary mechanism through which NODAL modulators exert their influence is by either enhancing or inhibiting these signaling pathways.
In summary, the recitation of Nodal agents in the claims represents an invitation to the skilled artisan to design and test such agents for the ability to treat infertility without providing any guidance as to their structure.
As an example of the encompassed antibody variants, the claims recite Adnectinstm, which describe single-domain antibody like structures without disulfide bonds. In the instant case, these structures have the function of binding and antagonizing activin A, activin B or activin AB. The reference by Lipovšek (cited above) defines the process of Adnectin discovery (p. 7, left column, last 2 paragraphs, citations omitted by examiner):
The steps that lead from human 10Fn3 to therapeutic Adnectins include:
(i) design and construction of 10Fn3-based libraries;
(ii) selection of target-binding molecules from the library using in vitro display;
(iii) screening of selected sequences for predicted immunogenicity;
(iv) screening of individual selected, bacterially produced proteins for favorable biophysical properties, including detailed binding kinetics, epitope-mapping, stability and solubility;
(v) screening of the proteins for in vitro activity in cell-based assays;
(vi) optimization of selected Adnectins by focused re-diversification and re-selection;
(vii) modification for improved pharmacokinetics;
(viii) characterization of biological efficacy in animal models; [and]
(ix) clinical trials in human patients.
In addition, detailed structural characterization of Adnectin-target complexes using X-ray crystallography continues to inform the discovery process, especially library design and optimization strategies.
While the 10Fn3 structure may be generally known, Lipovšek suggests a long process for designing and generating Adnectinstm, which again, represents an invitation to one skilled in the art to design and test such antibody variants.
Regarding proteins generally, the number of mutations generally possible in any given protein that can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g., such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. The art provides evidence that mutations can be destabilizing and their effects unpredictable. Bhattacharya et al. (PLoS ONE 12(3): e0171355. https://doi.org/10.1371/ journal.pone.0171355; 22 pages total) teach even single nucleotide variations have a “range of effects at the protein level that are significantly greater than assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge” (p. 18, 1st and 2nd paragraphs). In addition, Fenton et al. (Medicinal Chemistry Research (2020) 29:1133–1146) review the unpredictability of making substitutions at non-conserved positions in a protein, which can have significant effects on protein function, that computational algorithms cannot predict very well (p. 1134, right column, middle paragraph). In the instant case, the specification provides no guidance to enable one of ordinary skill in the art to determine, without undue experimentation, the derivatives of these proteins and antibodies and as such is merely an invitation to the artisan to use the current invention as a starting point for further experimentation.
Regarding the recitation of RNA interference towards FSH, FSH receptor alpha and/or beta expression; ActRIIA, ActRIIB, Alk4, Smad2, Smad3, Activin A and/or Activin B, relevant literature indicates that gene therapy with antisense, siRNA and shRNA is complex. For instance, the review by Hu et al. (Signal Transduction and Targeted Therapy (2020) 5:101) provides background on the state of the art of siRNA therapy. Hu et al. outline the challenges to siRNA therapy (p. 2, left column, 2nd paragraph):
Although siRNA holds promising prospects in drug development, several intracellular and extracellular barriers limit its extensive clinical application. Naked and unmodified siRNA possesses some disadvantages, such as (1) unsatisfactory stability and poor pharmacokinetic behavior and (2) the possible induction of off-target effects. The phosphodiester bond of siRNA is vulnerable to RNases and phosphatases. Once it is systematically administered into circulation, endonucleases or exonucleases throughout the body will quickly degrade siRNA into fragments, thus preventing the accumulation of intact therapeutic siRNA in the intended tissue. In theory, siRNA only functions when its antisense strand is completely base-paired to the target mRNA. However, a few mismatches are tolerated by the RNA-induced silencing complex (RISC), which may lead to undesired silencing of those genes with a few nucleotide mismatches.
Hu et al. review the techniques undertaken to deal with the challenges of siRNA therapy, which serve to underscore the complexity of the field. For instance, base modification is a promising technique, but one that is “basically at the stage of research and development” (see discussion under “Base modification in the paragraphs bridging the left and right columns of p. 6). Regarding siRNA delivery, Hu et al. teach:
Only 1–2% of internalized LNP [lipid nanoparticle]-loaded siRNAs were released into the cytoplasm, and this only occurred within a limited time frame after internalization. Hence, further understanding the escape mechanism and how to enhance the escape efficiency is of great importance for siRNA drug development (p. 11, left column, 1st paragraph). Citations omitted by examiner.
In spite of progress made in the field of siRNA drug development and delivery, Hu et al. underscore the complexity of a field that is still in its developmental stage.
In summary, the amended claims encompass a large genus of proteins, peptides, antibodies, small molecules and RNAi technologies for the treatment of infertility, but leave the discovery of this genus of agents up to the skilled artisan. However, patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be patentable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. Reasonable detail must be provided in order to enable members of the public to understand and carry out the invention. See Genentech v. Novo Nordick A/S (CAFC) 42 USPQ2d 1001 (1997).
Due to the large quantity of experimentation necessary to develop and test the encompassed proteins, peptides, antibodies, small molecules and RNAi technologies that lower FSH levels and activity and act as activin pathway modifying agents for the ability to treat infertility, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite limitations on the recited FSH-lowering and APM agents, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Notice for all US Patent Applications filed on or after March 16, 2013: In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 4, 7, 11, 20-22 and 26-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bernstein et al. (Endocrinology, 2016, 157: 1234-1247—first published online 12/29/2015—on IDS filed 10/05/2021). Since the current claim set has an effective filing date of 03/03/2026, the declaration under 37 CFR 1.130(a), stating the Bernstein abstract is not prior art to a claimed invention under AIA 35 USC 102(a)(1), is no longer relevant since the reference by Bernstein and colleagues was published over a year before 03/03/2026.
Bernstein et al. teach administration of ActRIIB:Fc to a mouse model for advanced maternal age suppresses FSH concentration, reduces oocyte aneuploidy and restores egg yields to the levels of younger mice (see p. 1239, Figure 4; also p. 1240, Figures 5A-5B; p. 1241, Figure 6, p. 1243, Figure 7), thereby meeting limitations set forth in claims 1, 20 and 26. The table at 5B shows that midlife mice treated with ActRIIB:Fc had significantly more total eggs as well as viable eggs than untreated controls. In addition, Bernstein et al. teach administering a bolus dose of hCG to trigger ovulation (see p. 1242, right column, 1st paragraph), thereby meeting limitations set forth in claim 4. Bernstein et al. report the ActRIIB:Fc was administered for at least two consecutive estrous cycles or alternatively, 19-24 days, which is equivalent to 3-4 cycles (see Bernstein et al., p. 1237, left column, 1st paragraph; right column, 1st paragraph; p. 1239, Figure 4 and right column), thereby meeting limitations in claims 20-22 and 27-30. Finally, Bernstein et al. do not teach administration of FSH to the mice.
Claims 1, 7 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bernstein et al. (Fertility and Sterility, (September 2015) Vol. 104, No. 3, SUPPL. 1, pp. e63. Abstract Number: O-161—hereafter “the Bernstein abstract”—on IDS filed 10/05/2021). Since the current claim set has an effective filing date of 03/03/2026, the declaration under 37 CFR 1.130(a), stating the Bernstein abstract is not prior art to a claimed invention under AIA 35 USC 102(a)(1), is no longer relevant since the Bernstein abstract was published over a year before 03/03/2026.
The Bernstein abstract teaches that in a midlife mouse model ActRIIB:Fc reduced FSH levels to those of younger animals in the midlife mouse model (SAMP8). In addition, the Bernstein abstract reports:
ActRIIB:Fc decreased chromosome misalignments from 32/193 (16.5%) to 11/159 (6.9%; P=0.0030), and decreased spindle misalignments from 13/192 (6.77%) to 4/155 (2.58%; P=0.0182). Rates of chromosome and spindle misalignments were lowered to those of young mice. ActRIIB:Fc restored nearly 40% of the fertility lost with age, increasing litter sizes from 5.06 to 6.29 pups/litter (P=0.0305, vs. 8.22 in young SAMP8).
See abstract RESULTS (4th paragraph). Thus, the Bernstein abstract teaches that ActRIIB:Fc was not only effective in reducing FSH levels, but also reducing aneuploidy. In addition, the Berstein abstract does not teach the administration of FSH, but rather PMSG (i.e., eCG). Although the Bernstein abstract does not explicitly teach an effect on the oocyte production, it does disclose an increase in the size of the litters, which suggests a greater number of oocytes. Furthermore, the Bernstein abstract teaches the same patient population being administered the same agent, thus any effects must inherently occur. See Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993) and Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846). In summary, the treatment methods set forth in the Bernstein abstract must, by definition achieve the same clinically significant improvements as recited in the claims absent evidence to the contrary.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 7, 11, 20, 26 and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Gleicher et al. (20170227554; effectively filed 4 March 2015—provisional patent application No. 62/128,127—of record). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Gleicher et al. teach the administration of anti-Müllerian hormone to human females undergoing in vitro fertilization to improve oocyte yield and pregnancy rates (see claims 1; 8; also paragraphs [0020] and [0177] of the PGPUB). See also p. 2, lines 14-18; p. 5, lines 5-8; p. 19, lines 11-13; p. 20, lines 5-6 of the ‘127 provisional. While Gleicher et al. teach superovulation may be carried out by administering FSH, they also teach it may be achieved using gonadotropin or luteinizing hormone (see claim 11). In summary, Gleicher et al. explicitly teach reducing incidence of infertility.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Gleicher et al. do not explicitly disclose the infertility results from oocyte aneuploidy, embryonic aneuploidy, and/or fetal aneuploidy. Nevertheless, Gleicher et al. teach that aneuploidy is associated with miscarriage and infertility and that their surprising finding is that “best” AMH levels are “associated with unexpectedly high clinical pregnancy and delivery rates in all age categories, reaching 17-18% clinical pregnancy even in women ≥43 years…[and facilitate] pregnancy and delivery chances” (see paragraph 0028]). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention that achieving ideal AMH levels in an assisted reproductive setting benefits an infertile patient population resulting from oocyte aneuploidy, embryonic aneuploidy, and/or fetal aneuploidy because Gleicher et al. demonstrate that “best” AMH levels are associated with increased pregnancy and live births. The person of ordinary skill in the art would have been motivated to treat this patient population with AMH because they have a particularly high failure rate in an IVF setting. Furthermore, the person of ordinary skill in the art could have reasonably expected success because of the improved live birth rates.
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
Claims 1, 4, 7, 11, 20-22 and 26-30 are rejected and claims 24, 25 and 31 are objected to.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675