DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 06/15/2023, has been entered.
Claims 1-5, 7-8, 15-24, 27-29 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I and species NB146-54 (SEQ ID NO: 16 in Table 8) in the reply filed on 03/13/2026 is acknowledged.
Claims 16-22, 24, 28-29 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Inventions, there being no allowable generic or linking claim.
Claims 1-4, 7-8, 15, 23, 27 are currently under examination as they read on an antibody specifically binding to Her2.
Independent Claim
1. (Original) An antibody or an antigen-binding fragment specifically binding to Her2, wherein the antibody or the antigen-binding fragment comprises a CDR1, a CDR2 and a CDR3; the CDR1, the CDR2 and the CDR3 comprise an HCDR1, an HCDR2 and an HCDR3 in a VHH domain set forth in any one of SEQ ID NOs: 16-33, respectively.
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.
Claims 3-5 are 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.
Independent claim 1 is directed to an antibody having CDRs1-3 as set forth in any one of the reference sequences. Dependent claims 3-5 defines the antibody having any mutations in the CDRs. The scope of claims 3-5 is broader than claim 1 as it encompasses plethora of variants of the antibody of claim 1. Therefore, the dependent claims are rejected for failure to further limit the subject matter of the claim upon which they depend.
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.
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 2-5, 7-8, 15, 23 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 2, 5, 7, 8, 15, 23 recite narrower “optionally” and/or “preferably” limitations that are preceded by broader limitations. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Therefore, the metes and bounds of the claim are ambiguous and ill-defined.
Furthermore, claim 2 improperly refers to Table a as the members of a Markush group. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) MPEP section 2173.05(s).
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 1-4, 7-8, 15, 23, 27 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.
The present claims are directed to an antibody that binds Her2 and has a CDR1, CDR2 and CDR3 selected from any HCDR1-3 in VHH domains in any of the reference sequence as recited. The combination of possible CDR1-3 encompassed by the breadth of the claims is endless and far exceeds the instant disclosure. Furthermore, the present claims recite an antibody not a VHH antibody. Therefore, the specification does not provide sufficient written support for a genus of antibodies with only CDRs of the heavy chain define. The present claims do NOT satisfy the written description requirement for the claimed genus for the following reasons:
The written description requirement for a claimed genus/subgenus may be satisfied through description of 1) a representative number of species OR 2) disclosure of relevant identifying characteristics, i.e., functional characteristics coupled with a known or disclosed correlation between function and structure.
Representative Species
With regard to representative number of species, the instant specification disclosed a number of species of the genus (Table 9). However, the disclosed species are not sufficient to represent the entire genus as claimed.
A “representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The “structural features common to the members of the genus” needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural “stepping stone” to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The size of the claimed antibody genus comprises substantial variations as one of skill in the art is well aware of the high level of polymorphism and complex nature of immunoglobulins. Schroeder et al. taught that through somatic variation, combinatorial rearrangement of individual gene segments and combinatorial association between different L and H chains, the repertoire of antibody diversity can have greater than 1016 different immunoglobulins (J Allergy Clin Immunol 2010, 125:S41-S52).
Moreover, it is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that over hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Therefore, the disclosed species are not representative of the claimed genus encompassing the substantial variation due to the high level of polymorphism of antibodies as exemplified by the above references.
Structure-function correlation
Written description can also be satisfied with disclosure of relevant identifying characteristics, i.e., functional characteristics coupled with a known or disclosed correlation between function and structure. While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function because antibody CDRs are necessary for binding and they are highly diverse in structure and their sequence does not correlate to binding in a predictable fashion. The subgenus as recited in claim 30 encompasses more than 220,000 possible variants with substitutions in the CDRs. The Applicant does not have possession of all these variants as not all of them will have the binding function as required by the claims.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually 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. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. 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. 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 as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff et al. teach 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. MacCallum et al. (J. Mol. Biol. 1996 262, 732-745), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology (2002) 169, 3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307:198-205), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (J. Mol. Biol. (2002) 320, 415-428), additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Chen et al. (J. Mol. Bio. (1999) 293, 865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol. (1999) 294, 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. Padlan et al. (PNAS 1989, 86:5938-5942) described the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen. In addition, Lamminmaki et al. (JBC 2001, 276:36687-36694) describe the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding). Recently, studies have shown that changing in CDRs even alter Fc binding to the Fc receptor and pharmacokinetics (Piche-Nicholas et al. MABS 2018, 10:81-94).
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of binding agents that bind HER2 broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-5, 7, 23, 27 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ren et al. (US Patent 11,617,767 B2).
Ren et al. taught a Her2-binding VHH nanobody comprising an amino acid sequence identical with elected species NB146-54 (SEQ ID NO: 16) (see Ren et al. column 14, lines 37-41; and sequence alignment below). Given that the prior art taught the same VHH antibody sequence, it would have identical CDRs1-3 and FR sequences. Moreover, Ren et al. taught a pharmaceutical composition and a kit comprising the VHH antibody (see, e.g., column 57, lines6-10).
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Claim 3-5, 7 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Revets et al. (US Patent 8,975,382 B2).
Revets et al. taught single domain antibodies that binds Her2 (see column 20, lines 65-68; sequence alignment). Given the language of mutation and percent identity recited in the present claims, Revets’s antibody anticipate the present claims.
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Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 8 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (US Patent 11,617,767 B2) in view of Revets et al. (US Patent 8,975,382 B2).
The teachings of Ren et al. have been discussed above (see 102). Ren et al. did not teach the antibody is 1) chimeric, humanized or fully human; and 2) multispecific. However, it would have been obvious to one of ordinary skill in the art to make a humanized antibody or a multispecific antibody as they are well known in the art before the effective filing date of the claimed invention. For example, Revets. Et al. taught humanized VHH antibodies that binds Her2 (column 21, lines 55-65) and multispecific antibody (column 192, lines 50-65).
The rationale to support a conclusion that the claims would have been obvious is that all the claimed elements (anti-Her2 VHH antibody and humanized and multispecific antibody) were known in the prior art and one of skilled in the art would have arrived at the claimed invention by using known methods with no change in their respective function and the combination would have yielded nothing more than the predictable result of making an anti-Her2 VHH antibody that is humanized or multispecific.
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention as evidenced by the references, especially in the absence of evidence to the contrary.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
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/SHARON X WEN/Primary Examiner, Art Unit 1641
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