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 without traverse of a method of reducing autoreactive autoantibodies in an individual comprising administering an FcRn inhibitor, wherein the FcRn inhibitor is an antibody or antigen binding fragment or polypeptide that binds to FcRn in the reply filed on 11/26/2025 is acknowledged. Applicant further elects without traverse a pregnant individual who is not a surrogate from Species Group B, nipocalimab (M281) from Species Group C, and YBX1 from Species Group D.
Claims 108, 115, and 120-135 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/26/2025.
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.
Written Description
Claims 105-107, 113, 114, and 116-119 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.
Claim 105 does not recite sufficient structural details-particularly six non-degenerate CDR sequences- for the broad genus of antibodies that are correlated with the function of binding to FcRn and inhibiting FcRn in order to reduce autoreactive antibodies in a pregnant individual. All claims dependent on claim 105 do not cure the deficiencies of claim 105 and are thus also rejected.
Claim 119 also does not recite any specific amino acid substitutions that can be made in the Fc domain of the claimed anti-FcRn antibodies such that the resulting variant Fc molecule (or FcRn binding fragment thereof) exhibits increased binding to FcRn relative to wild-type IgG Fc region.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 105 is broadly drawn to a method of reducing autoreactive antibodies in a pregnant individual comprising administering an FcRn inhibitor to the individual thereby reducing the autoreactive antibodies in the pregnant individual, wherein the FcRn inhibitor comprises an antibody or antigen-binding fragment thereof that binds to an FcRn. The overall therapeutic outcome of the claimed method is prevention or reduction of ASD symptoms in the offspring as recited in claim 114. Thus, the claimed anti-FcRn antibodies have the additional function of preventing or reducing ASD symptoms in the offspring of a pregnant individual.
It is well-known in the art that, in order to bind antigen, a conventional antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, “The Interaction of the Antibody Molecule with Specific Antigen”, section 3-6). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chain, and not either alone, that determines the final antigen specificity. As presently written, however, claim 105 does not recite the amino acid sequences of six non-degenerate CDRs for the genus of antibodies having the functional property of binding to FcRn and inhibiting FcRn function in order to reduce maternal autoantibodies against a embryonic or fetal CNS target in a pregnant individual, thereby preventing/reducing ASD symptoms in the offspring While Applicant has disclosed examples of anti-FcRn antibodies such as nipocalimab (M281) (see, e.g. Para. 0210), such disclosure does not adequately represent the structural diversity of the broad genus of antibodies that bind to FcRn and inhibit FcRn function in order reduce maternal autoantibodies against an embryonic or fetal CNS target in pregnant individuals, thereby preventing or reducing ASD symptoms in the offspring. Indeed, the working examples are limited to the use of Fc-engineered IgG variants (Abdegs) comprising specific Fc region amino acid substitutions (e.g. SEQ ID NOs: 1-3, YTEKF mutations) that increase FcRn binding affinity relative to wild-type IgG Fc (Example 3). The claimed genus also encompasses antibodies that can inhibit FcRn by binding to different epitopes; however, neither the specification nor prior art appears to sufficiently disclose a representative number of species for the genus of anti-FcRn antibodies that bind to different epitopes yet possess the claimed functional properties.
Further, claim 119 does not does not recite any specific amino acid substitutions that can be made in the Fc domain of the claimed anti-FcRn antibodies such that the resulting variant Fc molecule (or FcRn binding fragment thereof) exhibits increased binding to FcRn relative to wild-type IgG Fc region. The specification appears to only disclose Fc variants containing YTEKF substitutions (see, e.g. Para. 0010), and the working examples are limited to antibodies comprising these particular Fc mutations (Example 3). YTEKF mutations are not representative of the diversity of Fc substitutions that can be made in order to yield a variant Fc having increased affinity for FcRn. Artisans would not be able to readily determine without further testing which specific amino acid alterations can be made Fc domain or an FcRn binding fragment thereof to yield a variant Fc molecule that binds to FcRn with increased affinity relative to wild-type IgG Fc domain.
Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of anti-FcRn antibodies and variant Fc molecules at the time the instant application was filed.
Enablement
Claims 105-107, 109-114, and 116-119 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are broadly drawn to a method of reducing maternal autoreactive antibodies to a central nervous system (CNS) target present in an embryo or fetus (independent claim), wherein the method prevents or reduces symptoms associated with autism spectrum disorder (ASD) in the offspring (claim 116). As such, the claims encompass the reduction of maternal autoantibodies directed against any generic embryonic or fetal CNS target, including reduction against a single CNS antigen such as YBX1, without limitation to particular targets or combinations of targets associated with ASD.
The specification teaches that administration of Abdegs – FcRn antagonists comprising variant IgG Fc regions with increased FcRn binding affinity relative to wild-type IgG Fc—reduces maternal autoreactive antibodies targeting LDHA, LDHB, CRMP1, and STIP1 in MAR (maternal-autoantibody related)-ASD positive rodents generated by immunization with these antigens (Example 3). Prenatal exposure to MAR autoantibodies produced repetitive behaviors and reduced social interaction in exposed offspring, including impaired prosocial behavior and increased repetitive grooming (Example 4, Para. 0258, 0261-0263). Several prophetic examples are further provided for the preclinical evaluation of FcRn inhibitors such as anti-FcRn antibodies in the prevention of ASD-like phenotype in a pregnant/non-pregnant women and MAR rodent models (Examples 1-2 and Example 4, Para. 0264-0270).
There is no evidence provided in the specification that 1) reduction of maternal autoantibodies to any embryonic or fetal CNS target, regardless of pathological relevance, will prevent or reduce ASD symptoms in the offspring; 2) reduction of maternal autoantibodies against a single CNS target, as opposed to a defined combination of targets, is sufficient to prevent or reduce ASD symptoms in the offspring; and 3) reduction of maternal autoantibodies against YBX1 in particular will prevent or reduce ASD symptoms in the offspring commensurate in scope of the claims.
The prior art teaches that maternal autoantibody-related (MAR) autism is associated with maternal autoantibodies against a limited subset of fetal brain proteins. In particular, Edmiston et al identifies several candidate fetal brain antigens recognized by maternal autoantibodies and highly expressed in the developing fetal brain, including LDHA, LDHB, CRMP proteins, STIP1, YBX1, and cypin (Edmiston et al, see Introduction, 2nd paragraph). Numerous fetal CNS proteins exist that have not yet been implicated in ASD (Fountoulakis et al, see Abstract), and the specification provides no guidance for distinguishing pathogenic targets from non-pathogenic targets withing the full scope of the claims. Reducing maternal autoantibodies against CNS targets that are not pathologically relevant to ASD would not reasonably be expected to achieve the claimed therapeutic outcome.
As further described by Braunschweig et al, ASD risk and ASD-like phenotypes strongly correlate with distinct multi-antigen autoantibody profile, particularly combinations involving LDH, STIP1, CRMP1, and/or cypin, rather than isolated reactivity to individual antigens (Braunschweig et al see Abstract, Autoantibody Specificity, and Behavioral Correlations sections as well as Table 1). Consistent with these findings, the specification demonstrates ASD-like behavioral phenotypes in only the context of a specific pattern of maternal autoantibodies directed against multiple fetal brain proteins, including LDHA, LDHB, CRMP proteins, and STIP1 (Example 4). Although YBX1 is identified as one of several candidate fetal brain antigens recognized by maternal autoantibodies and highly expressed in the developing fetal brain (Edmiston et al , see Introduction, 2nd paragraph), the specification and prior art do not demonstrate functional involvement of YBX1-directed autoantibodies in producing ASD-like phenotypes. Thus, without further evidence, artisans would not reasonably expect that reduction of maternal autoantibodies against any single CNS target present such as YBX1 in an embryo or fetus, as encompassed by the claims, would be sufficient to prevent or reduce ASD symptoms in offspring. Artisans would necessarily have to engage in additional, unpredictable research to identify which CNS antigens, alone or in combination, are relevant to ASD prevention in the offspring of pregnant individuals.
Therefore, the specification does not enable the full scope of the claimed invention.
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.
Claims 105-107, 113, 114, and 116-119 are rejected under 35 U.S.C. 103 as being unpatentable over Fox-Edmiston et al (Fox-Edmiston, Elizabeth, and Judy Van de Water. “Maternal Anti-Fetal Brain IgG Autoantibodies and Autism Spectrum Disorder: Current Knowledge and its Implications for Potential Therapeutics.” CNS drugs vol. 29,9 (2015): 715-24. doi:10.1007/s40263-015-0279-2/0137713A1), hereinafter Edmiston.
Edmiston teaches that prenatal exposure to maternal autoantibodies directed against fetal brain proteins is a viable risk factor for the development of autism spectrum disorder (ASD) in the exposed offspring. Seven fetal brain proteins critical for neurodevelopment were identified as specific targets of maternal autoantibodies associated with maternal autoantibody-related autism, including Y-box binding protein (YBX1), lactate dehydrogenase (LDH) A and B, stress-induced phosphoprotein 1 (STIP1), collapsing response mediator proteins (CRMPs) 1 and 2, and cypin. Maternal IgG—including those that target these fetal brain proteins—cross the placenta via the neonatal Fc receptor (FcRn) during the third trimester (Abstract’ 1st, 2nd, and last paragraphs of Introduction; and Key Points); thus, it is suggested that FcRn inhibitors such as Abdegs (recombinant antibodies with engineered Fc regions having increased affinity for FcRn compared to wild-type IgG Fc) and anti-FcRn antibodies can be used to prevent the transfer of maternal anti-brain autoantibodies during critical periods of neurodevelopment, thereby preventing ASD in the offspring (see 1st paragraph under Section 2: Mechanisms to prevent of pathogenic autoantibodies; 1st and 3rd paragraphs of Section 2.2: In Vivo Antibody Competition and Removal, and Figures 2 and 3 captions). It is noted that Abdegs necessarily comprise a variant Fc region with one or more substitutions that increase affinity for FcRn relative to wildtype Fc region per claim 119. It is further stated that development of an autoantibody-based screening assay would enable identification of candidates in need of medical intervention (Section 3: Conclusions). Although the paper refers generally to “candidates for medical intervention”, the therapeutic strategies described are uniformly directed toward reducing or preventing the transfer of maternal autoantibodies to the developing fetus during gestation, necessarily limiting such candidates to pregnant women. Therefore, it would have been obvious for artisans to identify pregnant women who harbor autoantibodies against fetal brain proteins such as YBX1 by assaying a biological sample from the pregnant women and select those women for therapeutic intervention with FcRn-targeted therapies in order to prevent placental transfer of these pathogenic IgG, thereby preventing or reducing symptoms associated with autism or ASD in the offspring.
Claims 109-112 are rejected under 35 U.S.C. 103 as being unpatentable over Edmiston, as applied to claims 105-107, 113, 114, and 116-119 above, and further in view of Ling et al (Ling, Leona E et al. “M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study.” Clinical pharmacology and therapeutics vol. 105,4 (2019): 1031-1039. doi:10.1002/cpt.1276. EPUB: 2018 Dec 4), hereinafter Ling.
The teachings of Edmiston have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the anti-FcRn antibody therapy is nipocalimab (or M281).
However, Ling teaches that M281 (nipocalimab) is a high affinity, fully human, effectorles monoclonal IgG anti-FcRn antibody that inhibits FcRn-mediated IgG recycling to decrease pathogenic IgG while preserving IgG production. A consistent and close relationship has been observed between FcRn receptor occupancy, serum IgG reduction, and M281 pharmacokinetics. This, together with initial safety and tolerability data, supports further clinical evaluation of M281 in autoimmune and alloimmune diseases driven by pathogenic IgG autoantibodies (see Abstract, Study Highlights, and last paragraph of Introduction on Page 1032 prior to “Results” section).
It would have been obvious to one of ordinary skill in the art to use nipocalimab (or M281) as the FcRn antagonist in the method for prevention of autism spectrum disorder in the offspring of pregnant mothers as taught by Edmiston. One of ordinary skill in the art would have been motivated to do so since FcRn inhibitors such as anti-FcRn antibodies can be used to prevent the transfer of maternal anti-brain autoantibodies during critical periods of neurodevelopment, thereby preventing ASD in the offspring as taught by Edmiston; and nipocalimab (M281) is an anti-FcRn antibody that inhibits FcRn-mediated IgG recycling to decrease pathogenic IgG while preserving IgG production. Therefore, one of ordinary skill in the art would reasonably expect that administration of nipocalimab (M281) to pregnant mothers can prevent the transfer of maternal anti-brain autoantibodies- such as those targeting YBX1- in order to prevent or the reduce the risk of ASD in the offspring.
Claims 105-107, 109-114, and 116-119 are rejected under 35 U.S.C. 103 as being unpatentable over Van de Water et al (WO2011019929A1), hereinafter Van de Water, in view of Fox-Edmiston et al (Fox-Edmiston, Elizabeth, and Judy Van de Water. “Maternal Anti-Fetal Brain IgG Autoantibodies and Autism Spectrum Disorder: Current Knowledge and its Implications for Potential Therapeutics.” CNS drugs vol. 29,9 (2015): 715-24. doi:10.1007/s40263-015-0279-2/0137713A1), hereinafter Edmiston, and Ling et al (Ling, Leona E et al. “M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study.” Clinical pharmacology and therapeutics vol. 105,4 (2019): 1031-1039. doi:10.1002/cpt.1276. EPUB: 2018 Dec 4), hereinafter Ling.
Van de Water teaches methods for determining the risk of developing an autism spectrum disorder (ASD) in a fetus or child by detecting in a biological sample from the mother antibodies that bind to one or more biomarkers selected from the group consisting of Y Box Binding Protein 1 (YBX1), lactate dehydrogenase (LDH), guanine deaminase (GDA), collapsin response mediator protein 1 (CRMP1), stress-induced phosphoprotein 1 (STIP1), alpha subunit of the barbed-end actin binding protein Cap Z (CAPZA2), eukaryotic translation and elongation factor 1A1 (EEF1A1), microtubule-associated protein Tau (MAPT), dihydropyrimidinase-like protein 2 (DPYSL2), dynamin 1-like protein (DNM1L), radixin (RDX), moesin (MSN), and ezrin (EZR) (Abstract; Brief Summary of the Invention, in particular, Para. 0008). Further disclosed are methods of preventing or reducing the risk of a fetus or child developing an ASD by administering to the mother an agent that removes from the mother antibodies that bind to the one or more fetal biomarkers such as YBX1 (Abstract and Para. 0030). As such, the diagnostic and prevention and/or treatment methods are performed on a woman carry a fetus (i.e. who is pregnant) (Para. 0100).
Van de Water does not teach that the agent that facilitates removal of maternal autoantibodies targeting fetal biomarkers (e.g. YBX1) is an FcRn antagonists such as an Abdeg or the anti-FcRn antibody nipocalimab (M281).
However, Edmiston teaches that FcRn inhibitors such Abdegs (recombinant antibodies with engineered Fc regions having increased affinity for FcRn compared to wild-type IgG Fc) or anti-FcRn antibodies can be used to prevent the transfer of maternal anti-brain autoantibodies during critical periods of neurodevelopment, thereby preventing ASD in the offspring (see Abstract; last paragraph of Introduction prior to Section 2; 1st paragraph under Section 2: Mechanisms to prevent of pathogenic autoantibodies; 1st and 3rd paragraphs of Section 2.2: In Vivo Antibody Competition and Removal, and Figures 2 and 3 captions). It is noted that Abdegs necessarily comprise a variant Fc region with one or more substitutions that increase affinity for FcRn relative to wildtype Fc region per claim 119.
Ling further teaches that M281 (nipocalimab) is a high affinity, fully human, effectorles monoclonal IgG anti-FcRn antibody that inhibits FcRn-mediated IgG recycling to decrease pathogenic IgG while preserving IgG production. A consistent and close relationship has been observed between FcRn receptor occupancy, serum IgG reduction, and M281 pharmacokinetics. This, together with initial safety and tolerability data, supports further clinical evaluation of M281 in autoimmune and alloimmune diseases driven by pathogenic IgG autoantibodies (see Abstract, Study Highlights, and last paragraph of Introduction on Page 1032 prior to “Results” section).
It would have been obvious to one of ordinary skill in the art to use an FcRn antagonists such as an Abdeg or the anti-FcRn antibody nipocalimab (or M281) as the agent that facilitates removal of maternal autoantibodies against fetal biomarkers in the method for the prevention of autism spectrum disorder in the offspring of pregnant mothers as taught by Van de Water. One of ordinary skill in the art would have been motivated to do so since FcRn inhibitors such as Abdegs or anti-FcRn antibodies can be used to prevent the transfer of maternal anti-brain autoantibodies during critical periods of neurodevelopment, thereby preventing ASD in the offspring as taught by Edmiston; and nipocalimab (M281) is an anti-FcRn antibody that inhibits FcRn-mediated IgG recycling to decrease pathogenic IgG while preserving IgG production. Therefore, one of ordinary skill in the art would reasonably expect that administration of nipocalimab (M281) to pregnant mothers can prevent the transfer of maternal anti-brain autoantibodies- such as those targeting YBX1- in order to prevent or the reduce the risk of ASD in the offspring.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MICHAEL SZPERKA/ Primary Examiner, Art Unit 1641