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 .
Claims 1-20 are pending and will be examined on the merits.
Claim Rejections - 35 USC § 112
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 7-9 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.
Claims 7-9
Claim 7 recites the limitation "the nucleic acids of claim 5" in the body of the claim. There is insufficient antecedent basis for this limitation in the claim.
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 1-2, 5 and 10-20 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. This is a written description rejection.
Scope of the claimed antibodies
Instant claims 1 and 10-20
Instant claims 1 and 10-20 are directed to antibodies and antigen-binding fragments thereof capable of performing the recited function of specifically binding to citrullinated histone H3 (CitH3). Regarding the antibody structure required to perform this function, instant claim 1 recites that the instant claimed antibody comprises a VH having an amino acid sequence selected from the group consisting of instant SEQ ID NOs: 7, 8, 9 and 10 paired with a VL having an amino acid sequence selected from the group consisting of instant SEQ ID NOs: 11, 12 and 13. Additionally, instant claim 1 recites two selections of pairings of three VH CDRs with three VL CDRs:
1) VH CDR 1, 2 and 3 of instant SEQ ID NOs: 1, 2 and 3, respectively and VL CDR 1, 2 and 3 of instant SEQ ID NOs: 4, 5 and 6, respectively and
2) VH CDR 1, 2 and 3 of instant SEQ ID NOs: 16, 17 and 18, respectively and VL CDR 1, 2 and 3 of instant SEQ ID NOs: 19, 20 and 21, respectively.
Additionally, instant claim 1 permits up to 20% amino acid sequence variation in each of the numbered VH and VL CDR sequences. Instant claim 1 also does not provide any guidance or limitations regarding which amino acids may be selected for substitution or which amino acids are permitted to be selected as substitute/variant amino acids. As such, with instant claim 1 encompasses the genus of all antibodies capable of performing the recited function of binding CitH3 and comprising either of the two selections of six distinct CDR sequences recited in instant claim 1, wherein up to 20% of any of the amino acids in each of the six CDRs has been replaced with any other amino acid.
Instant claims 2 and 5
Instant claims 2 and 5 are directed to antibodies and antigen-binding fragments thereof capable of performing the recited function of specifically binding to CitH3. Regarding the antibody structure required to perform this function, instant claim 2 recites that the instant claimed antibody comprises a VH having an amino acid sequence selected from the group consisting of instant SEQ ID NOs: 7, 8, 9, 10 and 14 paired with a VL having an amino acid sequence selected from the group consisting of instant SEQ ID NOs: 11, 12, 13 and 14.
Additionally, instant claim 2 permits up to 10% amino acid sequence variation in the VH and/or VL amino acid sequences. Instant claim 2 also does not provide any guidance or limitations regarding which amino acids may be selected for substitution or which amino acids are permitted to be selected as substitute/variant amino acids. Instant claim 2 also imposes no limitations or restrictions regarding the loci of the amino acids to be selected for substitution, meaning instant claim 2 permits all of the up to 10% variant amino acids to be located within the binding-critical CDR regions. As such, instant claim 2 encompasses the genus of all antibodies capable of performing the recited function of binding CitH3 and comprising any of the VH sequences recited in claim 2 paired with any of the VL sequences recited in claim 2, wherein up to 10% of any of the amino acids in both the VH and VL sequences has been replaced with any other amino acid.
Description of Claimed Antibodies in specification
The instant Specification discloses a total of four humanized anti-CitH3 VH sequences as well as three humanized anti-CitH3 VL sequences, which can be found in Table 1 (Specification, Table 1, p 20):
VH1 (SEQ ID NO: 7)
VH2 (SEQ ID NO: 8)
VH3 (SEQ ID NO: 9)
VH4 (SEQ ID NO: 10)
VL1 (SEQ ID NO: 11)
VL2 (SEQ ID NO: 12)
VL3 (SEQ ID NO: 13)
Please note that all of the humanized VH and VL sequences discussed above share the same VH CDR and VL CDR sequences, with the Kabat CDR sequences being located in Table 2 of the instant Specification and are VH CDR 1, 2 and 3 of SEQ ID NOs: 1, 2 and 3 respectively and VL CDR 1, 2 and 3 of SEQ ID NOs: 4, 5 and 6, respectively (Specification, Table 2, p 21) and the Chothia CDR sequences being located in table 3 of the instant Specification and are VH CDR 1, 2 and 3 of SEQ ID NOs: 16, 17, and 18, respectively and VL CDR 1, 2 and 3 of SEQ ID NOs: 19, 20 and 21, respectively (Specification, Table 3, p 22).
The instant Specification also discloses that all of these VH and VL sequences were derived from mouse antibody Y1128, which comprises VH and VL sequences of SEQ ID NOs: 14 and 15, respectively (Specification, ¶ 0222). Please note that SEQ ID NOs: 14 and 15 also comprise the VH and VL CDRs disclosed in Tables 2 and 3. The instant Specification also teaches that any of the instant claimed VH variants may be combined with any of the instant claimed VL variants to form a functional antibody capable of performing the recited function of binding CitH3 (Specification, ¶ 0225). Additionally, the instant Specification also presents ELISA data demonstrating that all pairings (e.g., VH1/VL1, VH1/VL2, VH1/VL3, etc…) of the instant claimed VH and VL sequences form functional antibodies capable of performing the recited function of binding CitH3 (Specification, Table 4, p 49).
The instant Specification does not disclose any examples of antibodies comprising variant VH and/or VL CDRs comprising any of the explicitly disclosed CDR sequences with to 20% amino acid sequence variation from the explicitly disclosed sequences capable of performing the recited function of binding CitH3. The instant Specification does not disclose any examples of antibodies comprising variant VH and/or VL sequences comprising any of the explicitly disclosed VH or VL sequences with to 10% amino acid sequence variation (including variation in the CDR sequence regions) from the explicitly disclosed sequences capable of performing the recited function of binding CitH3.
State of the Relevant Art
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. Sela-Culang (Sela-Culang, et al., Front in Immunol. 2013; Vol. 4; Article 302) teaches on the subject of the structural basis of antibody-antigen recognition (Sela-Culang, Abstract). Sela-Culang teaches that there is a lack of intrinsic properties linking epitopic vs non-epitopic residues based on features present in said residues suggests that epitopes depend, to a great extent, on the antibody that recognizes them (Sela-Culang, p 2, ¶ 7). Sela-Culang teaches that antibodies fold in such a manner such that six hypervariable loops of the light and heavy domains of an antibody (three loops on the HC and three on the LC) are folded together and form the antigen binding site (Sela-Culang, p 3, ¶ 2). Sela-Culang teaches that the complimentary determining regions (CDRs) are amino acid sequences within this hypervariable region and that amino acids that define the CDR regions are typically defined based on numbering schemes (e.g., Kabat, Chothia, IMGT) derived from empirical studies of the boundaries between the framework and binding residues of the antibodies (Sela-Culang), p 3, ¶ 3). Sela-Culang teaches that identification of paratopes (the portion of an antibody which binds an antigen) is done through the identification of CDRs but CDRs, as identified by methods such as Kabat, Chothia and IMGT may miss ~20% of antigen binding residues (Sela-Culang, 4, ¶ 1-2). Sela-Culang teaches that each CDR has its own unique amino acid composition (i.e., different from the other CDRs) and each CDR has a unique set of contact preferences (Sela-Culang, p 5, ¶ 1).
Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict what an antibody with a particular set of functional properties would look like structurally. As discussed above, neither an epitope nor a paratope can be calculated a priori based on properties of the component amino acids. Furthermore, each and every CDR sequence is unique and distinct and, as such, a CDR sequence cannot be predicted, either from the epitope sequence of from the CDR sequences of the antibody, if known.
In addition to the importance of the CDR regions, Sela-Culang also teaches that framework residues are also play an important role in antigen binding (Sela-Culang, P 7, ¶ 3). These framework residues can be divided into two types. The first are framework residues that actually contact the antigen and therefore are part of the binding site (Sela-Culang, p 7 ¶ 4). The second type of framework residues that affect antigen binding are framework residues that do not directly contact the antigen but affect binding indirectly (Sela-Culang, p 7, ¶ 5). Some of the framework residues are in close proximity to the CDR regions of the parental antibody, with these FR residues providing structural support that permits the CDRs to adopt the right conformation to form the antigen binding.
The other type of framework residues that indirectly affect antigen binding are further from the CDR regions and affect the relative orientation of the VH and VL regions, and thus the orientation of the CDRs relative to each other (Sela-Culang, p 7, ¶ 6). Sela-Culang also teaches that the effect of framework residues on antigen binding is impossible to predict a priori. For example, Sela-Culang teaches that positions in FR-3 of the heavy chain affects the orientation of CDRH1 relative to CDRH2, however this is not always the case, as it has been shown that mutating a Lys in this region for either a Val, Ala or Arg resulted in affinity differences but no structural changes (Sela-Culang, p 7, ¶ 5).
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species that 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.
As discussed above, the instant Specification discloses that all possible pairings of the instant claimed VH and VL sequences form functional antibodies capable of performing the recited function of binding CitH3. However, given the fact that all of the disclosed antibodies share the same combination of six distinct CDR sequences, with respect to the binding-critical CDR regions, the instant Specification discloses one species of anti-CitH3 antibody comprising three distinct VH CDRs paired with three distinct VL CDRs that is capable of performing the required function of binding CitH3. A disclosure of a single combination of six distinct CDR sequences capable of forming a functional antibody capable of performing the required function of binding CitH3 is not sufficient to be representative of the astronomically large genus of variant antibodies comprising up to 20% sequence variation in all of the CDR sequences encompassed by instant claim 1 or the also astronomically large genus of variant antibodies comprising up to 10% sequence variation in the VH and VL sequences encompassed by instant claim 2.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody was the minimum structure essential for binding specificity and the framework residues also play a role in antigen binding and a disclosure of an antigen or epitope does not permit a skilled artisan to envision the structure an antibody would need to have to bind that antigen or epitope, even if the amino acid sequence of that epitope is known.
The teachings of Sela-Culang make very clear that a structure-function relationship between an antibody’s CDRs and the epitope it binds is not understood well enough to permit a skilled artisan to analyze an epitopic sequence and envision, a priori, the required CDR structure required to form a functional antibody capable of binding that epitope. Sela-Culang teaches that CDRs are independent structurally and each possess independent binding preferences. There is nothing in the present disclosure nor the prior art that would lead one of skill in the art to believe that the disclosure contains any new discoveries that would supplant these notions. The lack of known structure/function correlation between any given antibody’s VH and VL structure and that antibody’s ability to bind its respective antigen means that it is highly unlikely that a skilled artisan would be able to start with the CDR amino acid sequences of claim 1 or the VH and VL sequences of instant claim 2 and envision, a priori which, if any, of the variant CDR encompassed by instant claim 1 or the variant VH/VL sequences encompassed by instant claim 2 are capable of forming a function antibody capable of performing the required function of binding CitH3.
Because the species disclosed are insufficient to be considered representative of either the unfathomably large number of possible variations to the binding-critical CDR regions, coupled with the lack of established structure/function correlation, the claims lack written description and Applicant was not in possession of the invention as claimed.
Allowable Subject Matter
Claims 3-4 and 6 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
A multi-database, fused CDR sequence search was performed for the VH and VL CDR triplets shared by the sequences recited in instant claims 3 and 6. No 100% match was found in the prior art for either the VH or VL CDR triplets. The closest matches identified in the prior art for the VH and VL CDRs are depicted in the table below:
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200
400
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Greyscale
Please note that, in both cases, the next nearest prior art sequence identified was not associated with an anti-CitH3 antibody and, as such, it is unlikely that one of skill in the art would be motivated to start with either of the next nearest prior art sequences identified, perform the required amino acid substitutions required to arrive at the instant claimed VH and VL CDR sequences and pair the resultant VH and VL CDR sequences together to form a functional antibody capable of binding CitH3. As such, antibodies (or a nucleic acids encoding such antibodies) comprising VH CDR 1, 2 and 3 of SEQ ID NOs: 1, 2 and 3, respectively and VL CDR 1, 2 and 3 of SEQ ID NOs: 4, 5 and 6 are free of prior art and claims 3-4 and 6 would be otherwise allowable if not dependent on a rejected base claim.
Conclusion
Claims 1-2, 5 and 7-20 are rejected.
Claims 3-4 and 6 are objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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