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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10, 12, 14-16, and 19-24 and species: Fab molecule in the reply filed 12/15/2025 is acknowledged.
Claims 17-18, and 25-28, are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 12/15/2025.
Claims 1-10, 12, 14-16, and 19-24 are now under consideration in the instant Office Action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 1-10, 12, 14-16, and 19-24 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 1 is directed to an antigen-binding molecule that binds to any antigen as long as it results in maintained or increased C1q-binding activity. As such, the claim is directed to an antibody defined entirely by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen et al., 1995 (instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e., does not convey that Applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The specification discloses several combinations of sequences for bivalent antibodies in Tables 3 and 4. These antibodies are drawn to bind to the “HER2” antigen and include modifications to the Fc regions as indicated in the sequences listed. However, as discussed above, without any way to determine how broad the genus of such antibodies are, there is no way to determine if these antibodies represent the full breadth of what is claimed. The antibodies as claimed are drawn to no particular antigen at all, so long as the antigen binding arm of the instant claims can maintain or increase C1q-binding activity. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies. The instant claims encompasses an extremely broad range of antibodies ranging in the millions, and the instant specification does not provide adequate written description over the vast number of antibodies that are encompassed by the scope.
Further note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. This decision has precipitated guidance to the Office instructing that the portion of MPEP 2163 regarding the “newly characterized antigen test” (indicating a well-characterized antigen is sufficient to satisfy written description for antibodies which bind that antigen) should no longer be used and that contrary materials should not be relied upon as reflecting the current state of the law.
It is appreciated that certain claims do include some sites for amino acid substitutions of the Fc region variant. However, the instant claims do not recite sequences for the antigen binding portion, nor do they claim a specific antigen which the one armed binding molecule is required to bind to. The instant claims leave the entirety of the binding arm undefined, and includes variants which have no specific structure, the definition including any change to the structure so long as the function is retained.
However, as noted above, arbitrarily altering any amino acid in the CDR of an antibody is unpredictable and the specification does not convey possession of any CDRs other than those of the disclosed antibodies. Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs. Moreover, CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies. For example, WO 2008068048 (instant PTO-892) discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 (instant PTO-892) describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no evidence in the instant specification that a single CDR placed in the context of two to five other CDRS, regardless of what those other CDRs are, would result in the required function, nor that a single chain is correlated to the required function when combined with any other chain. As such, the specification fails to set forth a structure-function correlation sufficient to claim all possible antibodies defined by function and one-three CDRs or alterations thereof.
As such, the disclosure of several antibody sequences in the specification while the instant claims are drawn to any antibody bound by certain functional characteristics does not convey possession of other antibodies with the same binding properties; possession of the precisely defined sequence of six CDRs is required.
With respect to product claims 1-10, 12, 14-16, and 19-24, it is recognized that information which is well known in the art need not be described in detail in the specification (MPEP §2163(II)(A)(2)). See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention is in a new antibody, or at the least disclosure of a new antibody that could not have been envisaged from the prior art indicates that the prior art was not in possession of all “antigen-binding molecules that can maintain or increase C1q-binding activity”. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed, disclosing one antibody, does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
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., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as an antigen-binding molecule that can maintain or increase C1q-binding activity, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of antigen-binding molecules that can maintain or increase C1q-binding activity encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of antigen-binding molecules that can maintain or increase C1q-binding activity. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
To provide adequate written description and evidence of possession of the 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. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. 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 they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. 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 product 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.
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. 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).
Therefore, claims 1-10, 12, 14-16, and 19-24 do not meet the written description requirement.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-10, 12, 14-16, and 19-24 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Chugai et al. (WO 2018/052375 A1, in IDS filed 07/13/2023).
Chugai et al. discloses a polypeptide comprising a variant Fc region comprising at least one amino acid alteration in a parent Fc region, wherein the variant Fc region has a substantially decreased FcγR-binding activity and does not have a substantially decreased C1q-binding activity when compared to the parent Fc region (claim 8, Examples 4, 5). This meets the limitations of instant claim 1 wherein the antigen-binding molecule contains a variant Fc region that results in maintained or increased C1q-binding activity. Chugai et al. teaches that an "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments (pg. 12). This meets the limitations of instant claim 5 wherein the antigen-binding moiety comprises a Fab, scFv, VHH, etc. Chugai et al. also teaches that the antibody or antigen-binding molecules can be “used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity”, (pg. 12). This meets the limitations of instant claims 2, 3, and 4 wherein the antigen-binding moiety can bind to a different epitope than the first antigen binding moiety and the binding moieties are connected via the N-terminus. Chugai et al. also discloses the variant Fc region comprises Ala at position 234, Ala at position 235 and further amino acid alterations of any one of the following (a)-(c):
(a) positions 267, 268, and 324;
(b) positions 236, 267, 268, 324, and 332; and
(c) positions 326 and 333; according to EU numbering (claim 9),
and the variant Fc region comprises amino acids selected from the group consisting of:
(a) Glu at position 267;
(b) Phe at position 268;
(c) Thr at position 324;
(d) Ala at position 236;
(e) Glu at position 332;
(f) Ala, Asp, Glu, Met, or Trp at position 326; and
(g) Ser at position 333; according to EU numbering (claim 10).
This meets the limitations of instant claim 6 wherein the Fc region variants comprises Ala at position 234 and 235. This also meets the limitations of instant claim 7 wherein the Fc region variants comprise alterations at positions 267, 268, 326, 333, etc. This meets the limitations of instant claim 8 wherein the Fc region comprises variants including Glu at position 267, Glu at position 332, etc. Moreover, Chugai et al. discloses the variant Fc region further comprises amino acids selected from the group consisting of:
(a) Ala at position 434;
(b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(c) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(d) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440; according to EU numbering (claim 11).
This meets the limitations of instant claims 9 and 19 wherein Ala is substituted at position 434, Thr at position 436, Arg at position 438, and Glu at position 440. Regarding instant claims 10 and 20, given that the antibody invention of Chugai et al. teaches all the same substitutions as the instant invention, it would be expected that the functional limitations of hexamer formation based on the patterns of substitution is also achieved.
Chugai et al. teaches that the antibodies that comprise a variant Fe region of the present invention “can suppress antibody-dependent enhancement (ADE) observed with conventional anti-virus antibodies…Fc modifications that reduce interaction with activating FcγRs could alleviate the risk of ADE. Mutations at positions 234 and 235 from leucine to alanine to form LALA mutants have been shown to reduce the risk of ADE of dengue infection in vivo… such modifications, however, reduce the other effector immune functions mediated by antibodies, such as ADCC and CDC. Especially, CDC can be expected to play an important role in inhibiting ADE, therefore complement component C1q binding of Fe regions should not be reduced for therapeutic efficacy. Furthermore, antibody half-life can be extended by engineering Fe regions that change binding affinity to its salvage receptor, FcRn, which might lead to prophylactic use of antibodies for protecting viral infection”, (pg. 81). This meets the limitations of instant claims 12 and 21 wherein the antigen-binding molecule demonstrates a reduced risk to cause antibody-dependent enhancement of entry of a pathogen and recruits C1q to eliminate a pathogen or a cell infected by the pathogen via complement-dependent cytotoxicity.
Chugai et al. also discloses an antibody comprising the polypeptide (claims 13, 16), a pharmaceutical formulation comprising the polypeptide and a pharmaceutically acceptable carrier (claim 15), and an isolated nucleic acids encoding the antibody (p. 4, lines 23-24). This meets the limitations of instant claims 14-16 and 22-24 wherein a pharmaceutical composition comprising the antigen-binding molecule, an isolated nucleic acid encoding the antigen-binding molecule, and a host cell comprising the nucleic acid are taught.
Therefore, claims 1-10, 12, 14-16, and 19-24 are anticipated by Chugai et al.
Conclusion
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675