DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-2, 57-60, 232-235, 407-409, 411, 414, 419-420, 422, 425, 438, 441-442, 445-446 and 448 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(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 407 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 407 is directed to an antibody having a CDR combination permissible under the limitations of claim 1 and wherein the antibody is human or humanized. The instant Specification describes many rounds of humanization of various classes of mouse-derived antibodies (Specification, ¶¶ 0274, 0275, 0276 and 0277). The instant Specification does not, however, make any mention of fully humanizing any of the antibodies, a process where numerous amino acid residues in the CDR regions are altered to change the native murine CDR sequences to fully human sequences. Because the CDRs of claim 1 are all murine CDR sequences, claim 407 does not contain all of the limitations of claim 1 because claim 1 does not allow for the fully-human CDR sequences required for an antibody to be a human antibody.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 57-60, 232-235, 407-409, 411, 414, 419-420, 422, 425438, 441-442, 445-446 and 448 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, 407-409, 411, 414, 419-420, 422, 425-438, 441-442, 445-446 and 448
Instant claims 1, 407-409, 411, 414, 419-420, 422, 425-438, 441-442, 445-446 and 448 are directed to antibodies capable of performing the recited function of specifically binding to corticotropin-releasing hormone (CRH). Regarding the antibody structure required to perform this function, claim 1 recites that the antibody comprise three VH CDRs and three VL CDRs. Instant claim 1 permits VHCDR1 to be selected from any of SEQ ID NOs: 22-35, VHCDR2 to be selected from any of SEQ ID NOs: 53-78, VHCDR3 to be selected from any of SEQ ID NOs: 113-122 or the amino acid sequences PDV or GID and VLCDR1 to be selected from any of SEQ ID NOs: 152-174, VLCDR2 to be selected from any of SEQ ID NOs: 193-198, VLCDR3 to be selected from any of SEQ ID NOs: 223-232. Overall, instant claim 1 permits 14 options for VHCDR1, 25 options for VHCDR2, 11 options for VHCDR3, 22 options for VLCDR1, 5 options for VLCDR2 and 9 options for VLCDR3. As such, instant claim 1 is directed to 3,811,500 distinct combinations of three VH CDRs paired with three VL CDRs.
Instant claims 57-59
Instant claims 57-59 are dependent on claim 1 and further limit claim 1 by specifying the anti-CRH antibody comprises a VH selected from any one of SEQ ID NOs: 240-295, 459 and 461 and/OR a VL selected from 296-347 and 462. Claim 57 permits up to 10% sequence variation from the numbered sequences, claim 58 permits up to 5% sequence variation from the numbered sequences and claim 59 permits no sequence variation from the numbered sequences. Neither claims 57 nor 58 provide any limitations or guidance on where the variant amino acids are located or which amino acids are replaced with which, other than the variant amino acids not being permitted in the CDR regions by way of dependency on claim 1. Additionally, all of claims 57-58 only require either the numbered VH or the numbered VL to be present. That is to say, an antibody having a VH 90% identical to instant SEQ ID NO: 241 paired with any VL comprising any combination of VL CDRs permitted by claim 1 would satisfy claim 57.
Instant claim 60
Instant claim 60 is dependent on instant claim 59. Instant claim 60 recites a large number of specific VH and VL pairings, however each pairing only requires either the numbered VH or the numbered VL to satisfy the claim. That is to say, an antibody having a VH of SEQ ID NO: 241 paired a with any VL comprising any combination of VL CDRs permitted by claim 1 would satisfy claim 60.
Instant claims 232-234
Instant claims 232-234 are dependent on claim 1 and further limit claim 1 by specifying the anti-CRH antibody comprises a HC selected from any one of SEQ ID NOs: 348-403, 460 and 463 and/OR a LC selected from 404-455 and 464. Claim 232 permits up to 10% sequence variation from the numbered sequences, claim 233 permits up to 5% sequence variation from the numbered sequences and claim 234 permits no sequence variation from the numbered sequences. Neither claims 232 nor 233 provide any limitations or guidance on where the variant amino acids are located or which amino acids are replaced with which, other than the variant amino acids not being permitted in the CDR regions by way of dependency on claim 1. Additionally, all of claims 232-234 only require either the numbered HC or the numbered LC to be present. That is to say, an antibody having a HC 90% identical to instant SEQ ID NO: 348 paired with any LC comprising any combination of VL CDRs permitted by claim 1 would satisfy claim 232.
Instant claim 235
Instant claim 235 is dependent on instant claim 234. Instant claim 235 recites a large number of specific HC and LC pairings, however each pairing only requires either the numbered HC or the numbered LC to satisfy the claim. That is to say, an antibody having a HC of SEQ ID NO: 348 paired a with any LC comprising any combination of VL CDRs permitted by claim 1 would satisfy claim 235.
Description of Claimed Antibodies in specification
The instant Specification discloses a total of 173 antibodies capable of performing the recited function of binding CRH, each comprising six distinct CDRs, with the disclosure of all of the antibodies being found at Table 1 of the instant Specification, which spans pages 44-54 of the Specification and is reproduced below:
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601
974
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639
967
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647
975
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647
972
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624
971
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646
973
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638
967
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641
976
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630
974
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647
970
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243
986
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The instant Specification provides no father disclosure of additional antibodies capable of performing the required function of binding CRH.
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).
Additionally, at the time of filing, numerous anti-CRH antibodies were known in the art. Golde (Golde, et al., WO2019241127; Published 12/19/2019; Priority to 6/11/2018 via US 62/683,369) discloses anti-CRH antibodies which are conventional antibody and comprise six distinct CDRs (Golde, claims 2, 6).
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.
It is noted that a large number of antibodies with a wide range of CDR combinations is disclosed in the instant disclosure, however, the scope of the claimed genera eclipses the scope of the disclosed antibodies to a large degree. A disclosure of 173 distinct pairings of six CDRs forming functional anti-CRH antibodies is insufficient to be representative of the 3,811,500 CDR combinations encompassed by claims 1, 407-409, 411, 414, 419-420, 422, 425-438, 441-442, 445-446 and 448.
Claims 57-60, 232-235 are each directed to pairings comprising distinct HC CDR triplets paired with any combination of VL CDR triplets satisfying instant claim 1 as well as pairings comprising distinct LC CDR triplets paired with any combination of HC CDRs satisfying claim 1. While these genera are smaller than the 3,811,500 CDR combinations encompassed by instant claim 1, the disclosed species are still not adequate to reflect the scope of the genera. For example, if one starts with any of the VH or HC sequences of claims 57-60, 232-235, there is a genus of 990 combinations of LC CDRs satisfying claim 1 encompassed by the claims. Similarly, if one starts with any of the LC of VL sequences 57-60, 232-235, there is a genus of 3850 combinations of HC CDRs satisfying claim 1 encompassed by the claims. A disclosure of 173 distinct pairings of six CDRs capable of forming a functional antibody that can bind CRH is not sufficient to be representative of either genera.
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 any of the instant claimed partial sequences and arrive, a priori at a functional antibody capable of binding CRH.
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
Claim 2 is 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:
Instant claim 2 is directed to 50 anti-CRH antibodies, each comprising a distinct HC CDR triplet paired with a distinct LC CDR triplet. A fused sequence search was performed for each of the unique HC CDR triplets and LC CDR triplets recited in claim 2, with the next nearest prior art being identified in the table below:
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Please note that no prior art was found for the claimed antibody that binds to CRH comprising the recited VH-CDR1, CDR2, CDR3 sequences and VL-CDR1, CDR2, and CDR3 sequences of claim 1. As such, based on the state of the art, a skilled artisan cannot modify the next nearest prior art sequences (table above),to arrive at the instant instant claimed anti-CRH antibody. As such, anti-CRH antibodies having the distinct pairings of three VH CDRs paired with three VL CDRs recited in instant claim 2 are not obvious variants of the prior art and, as such, are free of prior art.
Conclusion
Claims 1, 57-60, 232-235, 407-409, 411, 414, 419-420, 422, 425, 438, 441-442, 445-446 and 448 are rejected.
Claim 2 is objected to.
No claims are allowed.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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