DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
2. The claims dated 4/30/2026 are under current examination. Claim 53 is amended. Claims 53-67 are pending in the instant application.
Election/Restriction
3. Applicant’s election of the antibody referred to as “Clone B” in the application (Table 3 having the heavy and light chain variable amino acid sequences), in the reply filed on 30 April 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
4. The requirement is deemed proper and is therefore made FINAL.
5. Claims 53-67, are being considered for examination in the instant application.
Drawings
6. Figures 10A-C are objected to because of the following informalities:
The title of these figures includes the term “Antigent Test” which appears to be an inconsistent terminology (emphasis added). The term “Antigent” is neither taught in the specification, nor is known in the relevant literature. Appropriate correction is required. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
7. The disclosure is objected to because of the following informalities:
8. The second sentence (para 0100) beginning “Also provided …...at least 85%” appears to be incomplete. There is also no period at the end of the sentence. Appropriate correction is required.
Claim Rejections - 35 USC § 112-Scope of enablement
9. 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.
10. The following is a quotation of the first paragraph of 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.
11. Claim 54 is rejected under 35 U.S.C. 112, first paragraph, because the specification while being enabling for an antibody or an antigen-binding fragment thereof, that specifically binds a H1.0K180me2 antigen protein or a peptide thereof, wherein the antibody comprises the heavy chain variable domain (VH) of SEQ ID NO: 7 and the light chain variable domain (VL) of SEQ ID NO: 9, does not reasonably provide enablement for an antibody that specifically binds said antigen, wherein the VH and VL of the antibody comprise at least 85% of the amino acid sequence of SEQ ID NO: 7 and at least 85% of the amino acid sequence of SEQ ID NO: 9, respectively. 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 the invention commensurate in scope with these claims.
12. Claim 54 is directed to an antibody or antigen binding fragment thereof that specifically binds a protein comprising an H1.0K180me2 antigen or a peptide thereof, wherein the antibody comprises the VH and VL comprising at least 85% of the amino acid sequence of SEQ ID NO: 7, and at least 85% of the amino acid sequence of SEQ ID NO: 9 respectively.
13. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, include the nature of the invention, the state of the prior art, the predictability or lack thereof in the art, the amount of direction or guidance present, the presence or absence of working examples, the breadth of the claims, and the quantity of experimentation needed. The instant disclosure fails to meet the enablement requirement for the following reasons:
14. With respect to claim breadth, the standard under 35 U.S.C. § 112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. In addition, when analyzing the enablement scope of the claims, the teachings of the specification are to be taken into account because the claims are to be given their broadest reasonable interpretation that is consistent with the specification (see MPEP 2111 [R-1]), which states that claims must be given their broadest reasonable interpretation.
15. “During patent examination, the pending claims must be “given their broadest reasonable interpretation consistent with the specification.” In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly that is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550-51 (CCPA 1969)”.
16. As such, the broadest reasonable interpretation of the claimed invention is directed to a genus of antibodies having at least 85% identity or similarity with each of the heavy and light variable domain amino acid sequences, and wherein such antibodies can specifically bind to H1.0K180me2 antigen.
17. The specification of the instant application describes antibodies that specifically bind to demethylated histone H1.0 antigen comprising a demethylated lysine residue (K180) of the full-length human histone H1.0 protein (H1.0K180me2) (para 0058, 0059). The specification teaches the development of a recombinant monoclonal antibody by immunizing rabbits against a H1.0K180me2 peptide, extraction of total cellular RNA from PBMC followed by RT-PCR of heavy and light chain variable domains, panning of cell surface library, selection of clones that bind to H1.0K180me2 and generation of full recombinant antibodies (para 0096; Examples 1-4; Fig. 1; Table 11). The specification describes the creation and sorting of five distinct antibody clones (Clones A, B, C, D, E) “in order of their specificity for H1.0K180me2” (para 0357), wherein instantly claimed Clone B (RW6), along with Clones A and C, are highly specific even in low concentrations with no cross-reactivity (para 0362; Example 3; Fig. 3). Table 3 (pages 20, 21) of the specification provides the VH and VL amino acid sequences (SEQ ID NOs: 7, 9) of antibody Clone B. The specification also states providing VH and VL sequences having at least 85% (para 0100) (As objected above, note that this sentence is incomplete.). Providing a sequence analysis of Clones A and B by conducting a pairwise sequence alignment of the variable domains of the two clones, the specification shows that the VH sequences share 61% identity, and the VL sequences share 83% identity (para 0368-0369; Fig. 5A, 5B). It is understood that the specification only describes the sequences for Clones A and B. The instant specification therefore, does not provide any guidance to antibodies having heavy chain and light chain variable domains comprising at least 85% of the amino acid sequence of SEQ ID NO: 7, and at least 85% of the amino acid sequence of SEQ ID NO: 9 respectively, wherein the recited genus of antibodies specifically bind to an H1.0K180me2 antigen protein. The instant specification does not teach how to make and use an antibody, which would have at least 85% of the VH and VL sequences (i.e. variants of VH, VL), and still be a functional equivalent of the unaltered antibody. Here the claims encompass antibodies reciting embodiments comprising variant VH and VL sequences, which are not fully defined. Undue experimentation would be required of the skilled artisan to make and use the said antibodies.
18. In the present case, the nature of the invention is complex. In contrast to the broad scope of the claim, what is provided in the specification is quite narrow. The specification discloses only Clone B antibody that contains the full length VH and VL amino acid sequences of SEQ ID NOs: 7 and 9 respectively, and which specifically binds to an H1.0K180me2 antigen protein. The specification also discloses four other antibodies (Clones A, C-E) that bind to H1.0K180me2 antigen. However, a 100% (or at least 85%) query match of the instantly claimed VH and VL sequences of H1.0K180me2 antibody was only present with SEQ ID NOs: 7 and 9 (see for example, submitted Appendix 1, 2 – 100% match highlighted). Note that while a 100% query match for SEQ ID NO: 9 (Appendix 2) was only seen with the instant application family, many results showed at least 85% query match with SEQ ID NO: 9, none of which however, are indicated as binding to an H1.0K180me2 antigen protein (as shown in the “Description” column). The specification therefore, does not enable variants of anti-H1.0K180me2 antibodies having altered sequences of VH and VL as instantly claimed.
19. The instant specification and claim 54 sweepingly state that the VH and VL of the antibody comprises at least 85% of the recited amino acid sequences, which means that the variability can exist in any region of the VH and VL including the CDR portions. It is well established in the art that the formation of an intact antigen-binding site of all antibodies requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, (textbook), 292-295, 1993), under the heading “Fv Structure and Diversity in Three Dimensions). It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, col 1, lines 3-8 and line 31 to col 2, line 9 and lines 27-30). In a 2023 review article, Patel et al (Human Antibodies 31: 71-80, 2023) teach that the specificity and high affinity of an antibody for an antigen-antibody interaction is primarily based upon the CDRs that are part of the VH and VL domain (page 72, col 1, para 2), as well as framework regions that exert a “significant impact on antibody affinity” (page 72, col 2, para 2). The reference teaches that approximately 20% of the residues binding the antigen are present outside of the CDRs, and are “equally essential to antigen binding as those found within the CDRs” (para spanning pages 76 and 77). Relevant literature also reveals that it is not predictable which amino acid residues within these (CDR, LC or HC) sequences can be changed and how they can be changed, i.e., by conservative or radical substitution, without disturbing the binding. An example of the unpredictability of making changes to the sequence of an antibody is provided by Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, 1982), who teaches that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. In particular, Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (see, for example, Abstract), thus demonstrating that each residue of the CDR is critical. Colman P. M. (Research in Immunology, 145:33-36, 1994) teach that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (page 35, top of col 1 and page 33, col 2). The relevant literature also reveals the unpredictability in the art as far demonstrating that any conservative substitution within any CDR can be made without affecting binding. For example, Brummell et al. (Biochemistry 32:1180-1187 1993) found that mutagenesis of the four HCDR3 contact residues for the carbohydrate antibody (Salmonella B O-polysaccharide) in no instance improved affinity but 60% of the mutants resulted in a 10-fold drop in binding constant (affinity electrophoresis value of 0.85), while still other mutants were lower (Table 1, page 1183, col 2, para 2 to page 1184, col 1, para 1). Brummell demonstrates that no substitution retained antigen binding affinity similar to the wild type antibody despite targeted, conservative substitutions in known contact sites. Thus, the art recognizes the unpredictability with respect to binding specificity of an antibody resulting from alterations in the amino acid sequences of the variable regions. It is unlikely that the antibodies and variants thereof as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions of a designated parental antibody have the required binding function. Therefore, while the skilled artisan could employ the teachings of the instant specification to make the instantly claimed H1.0K180me2 antibody having the VH, VL sequences comprising SEQ ID NOs: 7 and 9, neither the instant specification nor the knowledge in the art provide sufficient direction or guidance to enable the skilled artisan to produce the genus of anti- H1.0K180me2 antibodies encompassed by the instant claim which can comprise at least 85% each of said VH and VL sequences, and still have the specific binding ability of the parent antibody. The skilled artisan would not know, a priori, how to make H1.0K180me2 antibodies comprising non-identical VH and VL sequences for specifically binding to H1.0K180me2 antigen.
20. The instant claims therefore, encompass an invention of tremendous breadth, and essentially call for trial and error by the skilled artisan to begin discovering how to make the claimed invention without assisting the skilled artisan in such an endeavor, which amounts to undue experimentation and is therefore insufficient to constitute adequate enablement. The scope of the claims must bear a reasonable correlation with the scope of enablement. In re Fisher, 166 USPQ 18(CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Undue experimentation would be required to produce the invention commensurate with the breadth of the claims based on the disclosure of the instant specification and the knowledge in the art. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth.
21. Due to the large quantity of experimentation necessary to generate an H1.0K180me2 antibody having at least 85% of each of the claimed amino acid sequences of VH and VL, and which would specifically bind to H1.0K180me2 antigen; the unpredictability of maintaining binding characteristics of the claimed H1.0K180me2 antibody variants; the lack of sufficient direction/guidance presented in the specification regarding the same; the complex nature of the invention; and the state of the prior art which establishes the essential structural features of an antibody to maintain the antigen binding; and the breadth of the claims which fail to recite defined structural or functional limitations of the innumerable variants - undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Claim Rejections - 35 USC § 112 – Written Description
22. Claim 54 is rejected under 35 U.S.C. 112, 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, at the time the application was filed, had possession of the claimed invention.
23. The specification of the instant application describes antibodies that specifically bind to demethylated histone H1.0 antigen comprising a demethylated lysine residue (K180) of the full-length human histone H1.0 protein (H1.0K180me2) (para 0058, 0059). The specification teaches the developing of a recombinant monoclonal antibody by immunizing rabbits against a H1.0K180me2 peptide, extraction of total cellular RNA from PBMC followed by RT-PCR of heavy and light chain variable domains, panning of cell surface library, selection of clones that bind to H1.0K180me2 and generation of full recombinant antibodies (para 0096; Examples 1-4; Fig. 1; Table 11). The specification describes the creation and sorting of five distinct antibody clones (Clone A…Clone E) “in order of their specificity for H1.0K180me2” (para 0357), wherein instantly claimed Clone B (RW6), along with Clones A and C, are highly specific even in low concentrations with no cross-reactivity (para 0362; Example 3; Fig. 3). Table 3 (pages 20, 21) of the specification provides the VH and VL amino acid sequences (SEQ ID NOs: 7, 9) of antibody Clone B. The specification also states providing VH and VL sequences having at least 85% (para 0100) (As objected above, note that this sentence is incomplete.). Providing a sequence analysis of Clones A and B by conducting a pairwise sequence alignment of the variable domains of the two clones, the specification shows that the VH sequences share 61% identity, and the VL sequences share 83% identity (para 0368-0369; Fig. 5A, 5B). It is understood that the specification only provides the sequences for Clones A and B.
24. The specification however, does not have a written description of the genus of H1.0K180me2 antibodies that have at least 85% of the recited VH and VL sequences, and can specifically bind to H1.0K180me2 antigen. Note that the specification, by sequence analysis of Clones A and B reveals that between the two clones, the VH sequences share 61% identity, and the VL sequences share 83% identity. Moreover, as stated above, a 100% or at least 85% query match with the instantly claimed VH and VL sequences of the H1.0K180me2 antibody, was only shown by SEQ ID NOs: 7 and 9 of instant application (Appendix 1, 2). The functionally capable Clone B antibody provided in the specification, with the VH comprising SEQ ID NO: 7 and the VL comprising SEQ ID NO: 9, is not representative of the breadth of all antibodies of claim 54, or of a genus of the recited H1.0K180me2 antibodies that can specifically bind H1.0K180me2, even those not yet made.
25. Additionally, antibodies are quite diverse in their structure. Clone B antibody cannot possibly be the only representative of the genus of H1.0K180me2 antibodies having the recited sequences and specifically binding to H1.0K180me2 antigen, as it is a staggeringly large genus, given the number of possible permutations of amino acids in VH and VL that could be encompassed by the claims. Note that in AbbVie v Janssen (App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)), the court held that even though applicant was in possession of 300 different antibodies, those had all been derived from a single parent antibody, and the applicant was not in possession of the genus of antibodies that were encompassed by the claim. Given that there is a lack of predictability between the structure of the VH and VL and the function of binding, coupled with the lack of disclosure of species representative of the breadth of the genus, the written description requirement is not met.
26. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. Applicants are directed to the published guidelines on interpretation of the written description requirement, available on the internet at: www.uspto.gov/web/menu/written.pdf. The specification has not shown a relationship between the structure, function, or properties of the claimed genus of H1.0K180me2 antibodies. There is not even identification of any particular region of the VH and VL that must be conserved for binding to a H1.0K180me2 protein. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. The brief description in the specification of Clone B H1.0K180me2 antibody having the structural and functional features recited in claim 54, is not adequate written description of an entire genus of functionally equivalent antibodies that bind to H1.0K180me2 antigen.
27. The specification states that antibodies of the instant application can be produced by methods known to the skilled artisan, which include using recombinant cells engineered to express the desired VH, VL and constant regions, or hybridomas (para 0094). The situation is analogous to the decision in the University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004), wherein the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face. Since the specification does not disclose to the public the structures claimed, it does not meet the written description requirement of 35 USC § 112(a), first paragraph.
28. Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
29. Applicant has claimed a broad genus of antibodies comprising variants thereof. The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, "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 thereof. The court has further stated that adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, and not merely wish or plan for obtaining the claimed invention. [MPEP 2163(II)(A)(3)(a)]
30. 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).
31. With the exception of Clone B H1.0K180me2 antibody comprising SEQ ID NO: 7 (VH) and SEQ ID NO: 9 (VL), and specifically binding a H1.0K180me2 antigen protein, the skilled artisan cannot envision the detailed chemical structure of the encompassed H1.0K180me2 antibodies that have at least 85% of SEQ ID NO: 7, at least 85% of SEQ ID NO: 9, and can also specifically bind to said antigen, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation or production. 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 polypeptide 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.
32. 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.
33. Therefore, only Clone B antibody provided in the specification, but not the full breadth of claim 54 meets the written description provision of 35 U.S.C. §112, first paragraph. 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).
Sequence Search Analysis
34. All recited sequences have been searched. Following sequences are determined to be free of the prior dated art:
a) CDR sequences of the light chain variable domain (in fused or combined form of CDR1-CDR2-CDR3) comprising SEQ ID NOs: 12, 13, 16, 17, 19 (claim 53).
b) CDR sequences of the heavy chain variable domain comprising SEQ ID NOs: 25, 33, 34, 35.
c) VH sequence of SEQ ID NO: 7.
The only reference of said combination or sequence, is disclosed in related application/s from which the instant Application derives priority.
Claim Objections
35. Claim 55 is objected to as being dependent upon a rejected or objected base claim/s. Claim 55 depends from rejected claim 54. Claim 55 would however, be allowable if rewritten in an independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
36. Claims 53, 56-67 are allowable.
37. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aditi Dutt whose telephone number is (571)272-9037. The examiner can normally be reached on M-F 9:00am-5:00pm.
38. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
39. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker, can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/A. D./
Examiner, Art Unit 1675
21 July 2026
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
Prosecution Insights