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 .
Applicants’ preliminary amendment filed on June 21, 2024. Claims 1, 2, 4, 5, 7, 9, 12-17, 19, 24, 28, 30, 34, 36, 49, and 57 are pending and under examination in this Office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 28, 2026 has been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claims 1, 2, 4, 5, 7, 9, 12-17, 19, 24, 28, 30, 34, 36, 49, and 57 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 instant claims are directed to An antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region encoded by the heavy chain nucleic acid of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region encoded by the light chain nucleic acid of the same antibody clone of Table 1.
The claims are rejected because Applicant’s specification fails to provide an adequate written description for the genus of the claimed antibodies. There is a lack of structure and function correlation between the required binding and the specific structure that binds the antigen. Additionally, the claims lack the recitation of a specific antigen (such as an influenza virus antigen) to which the antibody binds.
The specification fails to provide an adequate written description an antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same antibody clone of Table 1.
In paragraph for example [0159] The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 16572, 17894, and 9536, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS:15890, 10705, and 12808, respectively.
The Specification contemplates changing amino acid within the heavy and light chain variable region, paragraph [2039] The following is a discussion of changing the amino acid subunits of a protein to create an equivalent, or even improved, second-generation variant polypeptide or peptide. For example, certain amino acids may be substituted for other amino acids in a protein or polypeptide sequence with or without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites on substrate molecules. Since it is the interactive capacity and nature of a protein that defines that protein's functional activity, certain amino acid substitutions can be made in a protein sequence and in its corresponding DNA coding sequence, and nevertheless produce a protein with similar or desirable properties. It is thus contemplated by the inventors that various changes may be made in the DNA sequences of genes which encode proteins without appreciable loss of their biological utility or activity.
The specification lists multiple species of antibodies [0033-1897] The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 17275, 18029, and 3941, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 16056, 9503, and 12778, respectively.
The instant specification does not provide an adequate written description for CDRs of a given antibody differing by up to 20% from the nature amino acid sequence for the given antibody as currently claimed.
[1965] Monoclonal antibodies or “mAb” refer to an antibody obtained from a population of homogeneous antibodies from an exclusive parental cell, e.g., the population is identical except for naturally occurring mutations that may be present in minor amounts. Each monoclonal antibody is directed against a single antigenic determinant.
[1966] Certain aspects relate to antibody fragments, such as antibody fragments that bind to flu antigens. The term functional antibody fragment includes antigen-binding fragments of an antibody that retain the ability to specifically bind to an antigen.
The prior art recognizes that the 6CDRs of an antibody are the portion of the antibody that primarily define the binding region of a given antibody. However, the instant specification does not adequately describe antibodies or antigen binding proteins that differ by as much as 20% from the native amino acid sequence of the disclosed antibody/antigen binding fragment. The specification further fails to provide any structure/function relationship for the recited CDRs and any possible mutation/alteration that would encompass up to 20% variation in the disclosed structures. It does not appear that the instant disclosure modified any of the isolated antibodies.
The structures of the antigen binding proteins claimed are not adequately described. In AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., Ill USPQ2d 1780 (Fed. Cir. 2014) AbbVie had claims to functionally claimed antibodies and Centocor presented evidence that the antibodies described in AbbVie's patents were not representative of other members of the functionally claimed genus. The decision states, “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.’ Id. at 1349. We have held that 'a sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus.’ Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). Here, the claimed invention is a class of fully human antibodies that are defined by their high affinity and neutralizing activity to human IL-12, a known antigen. AbbVie's expert conceded that the '128 and '485 patents do not disclose structural features common to the members of the claimed genus.”
The AbbVie decision considers how large of a genus is involved and what species of the genus are described in the patent. With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and ... cover any compound later actually invented and determined to fall within the claim's functional boundaries.”).
The specification provides no written description for CDR structures which differ from those which are disclosed as encompassed by the claim limitation of “having at least 80% sequence identity”. There is no written description for any antibody/antigen binding fragment with as much as 20% variation in amino acid sequence structure, as encompassed by the claims, nor have any functional antibodies which bind to particular target with such variation been described. Furthermore, claim 1 does not even recite what the antigen-binding fragment binds. There is no written description for making the multitude of encompassed CDRs recited with an expectation of obtaining an antibody or antigen binding fragment that has any particular functional activity. The state of the prior art is such that the formation of an intact antigen-binding site of antibodies routinely 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, 3rd Edition, 1993,
pp. 292-295, under the heading "Fv Structure and Diversity in Three Dimensions"). 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 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 maintaintheir 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, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). 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. (PNAS 79: 1979-1983, 1982). 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. 262: 732-745, 1996) 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 column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). De Pascalis et al. (J. Immunol. 169: 3076-3084, 2002) demonstrate that grafting 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 column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column). Thus, the art discloses that a change of even one amino acid of an antibody may change the ability of that antibody to bind to its original epitope. In addition, the art discloses that amino acids outside the CDRs are critical for antigen binding.
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. (Biochem. Biophys. Res. Comm. 307: 198-205, 2003) 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 column) and this is demonstrated in this work by using all CDRs except L32 and additionally using a framework residue located just before the H3 (see page 202, left column). Chen et al. (J. Mol. Biol. 293: 865-881, 1999) 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, CDRH1-H3 (page 866). Wu et al. (J. Mol. Biol. 294: 151-162, 1999) 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 column) but certain residues have been identified as important for maintaining conformation.
In the absence of sufficient direction and guidance, the disclosure of a specific antibody/antigen-binding fragment which comprises CDRs listed in Table 1. does not provide sufficient written description for the entire genus of antigen binding proteins which lack such sequences as encompassed by the claims in view of the evidence cited above.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, 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, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing 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.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.”
Thus, given the level of skill and knowledge and predictability in the art, those of skill in the art would not conclude that the applicant was in possession of the claimed genera of antibody variants based on disclosures set forth above. "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004). 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. See, e.g., Eli Lilly.
Further, it is not sufficient to define the genus solely by its principal biological property, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. Per the Enzo court's example, (Enzo Biochem, Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) couched "in terms of its function of lessening inflammation of tissues" which, the court stated, "fails to distinguish any steroid from others having the same activity or function" and the expression "an antibiotic penicillin" fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. (Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus, which are antigen binding proteins which vary from the disclosed antibody which comprises SEQ ID NOs listed in Table 1. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. The specification does not clearly allow those of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
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).
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.
Claims 1, 2, 4, 5, 7, 9, 12-17, 19, 24, 28, 30, 34, 36, 49, and 57 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.
The instant claims are directed to An antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region encoded by the heavy chain nucleic acid of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region encoded by the light chain nucleic acid of the same antibody clone of Table 1.
Tables within the claims is problematic. See 2173.05(s): 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).
Correction is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 2, 4, 5, 7, 9, 12-17, 19, 24, 28, 30, 34, 36, 49, and 57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,077,574. Although the claims at issue are not identical, they are not patentably distinct from each other because The instant claims are directed to An antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region encoded by the heavy chain nucleic acid of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region encoded by the light chain nucleic acid of the same antibody clone of Table 1.
The claims of the U.S. Patent No. 12,077,574 An antibody or antibody fragment comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 68, a CDR2 of SEQ ID NO: 70 and CDR3 of SEQ ID NO: 72, and a light chain variable region comprising a CDR1 of SEQ ID NO: 76, a CDR2 of SEQ ID NO: 78 and CDR3 of SEQ ID NO: 80 wherein the antibody or antibody fragment is capable of binding to influenza neuraminidase (NA) protein.
The present claims and the claims of the U.S. Patent No. 12,077,574 are drawn to antibodies binding influenza virus antigen.
Claims 1, 2, 4, 5, 7, 9, 12-17, 19, 24, 28, 30, 34, 36, 49, and 57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,077,573. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to An antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region encoded by the heavy chain nucleic acid of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region encoded by the light chain nucleic acid of the same antibody clone of Table 1.
An antibody or antibody fragment comprising a heavy chain variable region comprising a CDR1 of SEQ ID NO: 84, a CDR2 of SEQ ID NO: 86 and CDR3 of SEQ ID NO: 88, and a light chain variable region comprising a CDR1 of SEQ ID NO: 92, a CDR2 of SEQ ID NO: 94 and CDR3 of SEQ ID NO: 96 wherein the antibody or antibody fragment is capable of binding to influenza neuraminidase (NA) protein.
The present claims and the claims of the U.S. Patent No. 12,077,573 are drawn to antibodies binding influenza virus antigen.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Pertinent Prior Art
Taguchi et al. US 2019/0077860 teaches an amino acid sequence with 97.6% identity to SEQ ID NO: 7657 of the instant application.
Liu et al. US 2018/0057604 teaches an amino acid sequence with 94.7% identity to SEQ ID NO: 7657 of the instant application.
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/AGNIESZKA BOESEN/Primary Examiner, Art Unit 1648
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