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 .
DETAILED ACTION
Applicant’s election without traverse of Group I, claims 9, 10, 13, 14, 16-21, 32, 35, and 40 in the reply filed on 02/12/2026 is acknowledged. With respect to the species election requirement, Applicant has elected an anti-canine PD-1 antibody comprising the heavy chain CDRs of SEQ ID NO(s): 27, 34, and 36, respectively, and the light chain CDRs of SEQ ID NO(s): 13, 20, and 25, respectively.
Claims 9, 10, 13, 14, 16-21, 32, 35, and 40 are pending.
Claims 23, 25, and 33 are canceled.
Claim 35 is currently amended.
Claims 9, 10, 13, 14, 16-21, 32, 35, and 40 are under examination on the merits.
Notes on the Prior Art
At the effective filing date of the invention, antibodies specific for PD-1 were known in the art. For example Freeman et al. (WO 2014/022759, international filing date: 02/08/2013) teach anti-PD-1 blocking antibodies, see paragraph bridging p. 4 and 5. Furthermore at p. 25, lines 23-27, Freeman et al. teach non-human PD-1 orthologs, such as dog PD-1. Therefore at the effective filing date of the invention, one of ordinary skill in the art could have developed anti-dog PD-1 blocking antibodies; however the prior art does not teach a dog (or canine) antibody that comprises the CDRs recited in the base claim 35. Furthermore the instantly claimed anti-canine PD-1 antibodies are not an obvious variant of any art-known anti-canine PD-1 antibodies, and as such the instantly claimed anti-canine PD-1 antibodies are free of the prior art.
Claim Rejections
35 U.S.C. 112, First Paragraph
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 9, 10, 13, 14, 16-19, 21, 32, 35, and 40 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claim 35 is drawn to an isolated mammalian antibody or an antigen binding fragment thereof that binds canine Programmed Death Receptor 1 (canine PD-1) with specificity, said antibody comprising three light chain complementarity determining regions (CDRs) and three heavy chain CDRs. Claim 35 is drawn anti-canine PD-1 antibodies that may comprise a broad range of sequences. For example CDRL1 may comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 13, a conservatively modified variant of SEQ ID NO: 13, and a variant of SEQ ID NO: 13 that comprises the canonical structure class of 3. With respect to the recitation of a “conservatively modified variant of SEQ ID NO: 13,” for example, the specification defines conservatively modified variants (or conservative substitutions) as “substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g. charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity of the protein.” See p. 41 and 42. At Table 3, the specification provides numerous conservative amino acid substitutions that may be made for various amino acids, and in view of the breadth of said numerous conservative amino acid substitutions, the recitation of a “conservatively modified variant of SEQ ID NO: 13” encompasses many variants of SEQ ID NO: 13, including variant CDRL1 amino acid sequences having different numbers and types of amino acid substitutions. The claims further recite that each of CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 may be selected from a group of different amino acid sequences and conservatively modified variants thereof. Therefore the claims encompass a vast number of different anti-canine PD-1 antibodies having diverse light and heavy chain CDR sequences (and combinations of said CDR sequences). At p. 66-68, Applicant discloses light and heavy chain CDR sequences for seven anti-canine PD-1 antibodies: 1B5, 2G9, 2H9, 3B6, 4D12, 5G5, and 7C9; however in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass numerous PD-1-binding antibody species. Even though Applicant has disclosed multiple species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to antibody molecules capable of binding canine PD-1 and blocking the binding of canine PD-1 to canine Programmed Death Ligand 1 (PD-L1). Therefore the specification does not sufficiently describe the claimed genus such that the skilled artisan would conclude that Applicant was in possession of the claimed genus at the time of the invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which 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. In the instant case, Applicant has disclosed multiple species within the genus claimed; however given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of said species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region combinations that confer upon an antibody the ability to bind canine PD-1, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind canine PD-1. To elaborate on why the claimed antibodies lack adequate written description, Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987, in IDS from 06/13/2025) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody’s antigen-binding specificity. In view of Mariuzza, it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the antibody that correlates with the antibody’s ability to bind antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind canine-PD1 which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain variable region CDR amino acid sequences may be combined such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to bind canine PD-1.
Furthermore while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001, in IDS from 06/13/2025) demonstrated that a single heavy chain variable region CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79): 18294-18302, 2011, in IDS from 06/13/2025) teach that a single amino acid substitution in the heavy chain variable region of CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the heavy chain variable region CDR3 of ZL.80 with an alanine residue reduces antigen binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the heavy chain variable region CDR3 of ZL.80 may significantly improve binding. For example replacing the Val108 residue in the heavy chain variable region CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly absent empirical determination, one skilled in the art would be unable to predict or envision which of the claimed heavy and light chain variable region CDR residues could be changed such that a particular anti-canine PD-1 antibody variant maintains the ability to bind canine PD-1.
Applicant’s attention is also directed to the February 2018 USPTO Memorandum, subject: “Clarification of Written Description Guidance for Claims Drawn to Antibodies and Status of 2008 Training Materials,” hereafter referred to the “Memo.”
The Memo reads as follows:
I. Federal Circuit Clarification of the Law of Written Description As It Applies to Antibodies
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. These claims are usually handled in Technology Center 1600. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the ‘newly characterized antigen’ test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id. The Amgen decision will be added to the MPEP in due course.
II. Examples in the 2008 Written Description Training Materials Are Outdated
On March 25, 2008, the USPTO issued revision 1 of the Written Description Training Materials. As indicated on the USPTO web site at https://www.uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials, these training materials have been archived. Written description training materials containing examples that reflect developments in the law regarding 35 U.S.C. §§ 101 and 112 are being prepared. The archived training materials are outdated and should not be relied upon as reflecting the current state of the law regarding 35 U.S.C. §§ 101 and 112.
In the instant case, claims 13, 14, and 16 recite anti-canine PD1 antibodies that bind multiple amino acid sequences that are antigens comprised within canine PD-1. These antibodies lack adequate written description, because based upon the Memo, it is submitted that adequate description of an antigen to which an antibody binds is not sufficient to adequately describe the genus of antibodies specific for said antigen. Furthermore as indicated above, the USPTO Written Description Training Materials, dated 03/25/2008, have been archived and no longer reflect the current state of the law regarding 35 U.S.C. 112(a).
Therefore given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
Nonstatutory 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 9, 10, 13, 14, 16, 17, 32, and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,252,536.
With respect to the instant claims 32 and 35, although the claims at issue are not identical, they are not patentably distinct from each other, because both sets of claims encompass a caninized anti-PD-1 antibody comprising the heavy chain CDRs of SEQ ID NO(s): 27, 34, and 36, respectively, and the light chain CDRs of claims 13, 20, and 25, respectively, and an associated pharmaceutical composition.
With respect to claims 9 and 10, Example 2 of the specification for U.S. Patent No. 12,252,536 details the production of murine anti-canine PD-1 antibodies, and as such absent evidence to the contrary the heavy and light chain CDRs recited in claim 35 are murine sequences. Furthermore as indicated above the conflicting claims recite a caninized anti-PD-1 antibody.
With respect to claims 13, 14, and 16, given that the claims at issue comprise the same heavy and light chain CDRs, one of ordinary skill in the art would reason that the claims at issue have the same epitope specificities.
With respect to claim 17, given that the claims at issue comprise the same heavy and light chain CDRs but are not limited with respect to antibody framework regions, the claims at issue encompass a caninized anti-PD-1 antibody comprising the heavy chain CDRs of SEQ ID NO(s): 27, 34, and 36, respectively, and the light chain CDRs of claims 13, 20, and 25, respectively, and any framework region sequence. Different anti-PD-1 antibody species that comprise the heavy chain CDRs of SEQ ID NO(s): 27, 34, and 36, respectively, and the light chain CDRs of claims 13, 20, and 25, respectively, and different framework sequences would effectively all be expected to bind the same epitope and cross-compete with one another.
Claims 9, 10, 13, 14, 16-21, 32, 35, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,252,536 in view of Papadopoulos et al. (PG PUB 2015/0203579, publication date: 07/23/2015).
As indicated above, although the claims at issue are not identical, they are not patentably distinct from each other, because both sets of claims encompass a caninized anti-PD-1 antibody comprising the heavy chain CDRs of SEQ ID NO(s): 27, 34, and 36, respectively, and the light chain CDRs of claims 13, 20, and 25, respectively, and an associated pharmaceutical composition.
At [0047], Papadopoulos et al. teach “recombinant expression vectors capable of expressing a polypeptide comprising a heavy or light chain variable region of an anti-PD-1 antibody. For example, the present invention includes recombinant expression vectors comprising … nucleic acid molecules encoding any of the HCVR, LCVR, and/or CDR sequence…. The present invention also provides recombinant expression vectors capable of expressing a polypeptide comprising a heavy or light chain of an anti-PD-1 antibody. For example, the present invention includes recombinant expression vectors comprising … nucleic acid molecules encoding any of the heavy chain or light chain sequences... Also included within the scope of the present invention are host cells into which such vectors have been introduced, as well as methods of producing the antibodies or portions thereof by culturing the host cells under conditions permitting production of the antibodies or antibody fragments, and recovering the antibodies and antibody fragments so produced.”
Based upon these teachings, one of ordinary skill in the art would have been motivated to prepare nucleic acids that encode a caninized anti-PD-1 antibody comprising the heavy chain CDRs of SEQ ID NO(s): 27, 34, and 36, respectively, and the light chain CDRs of claims 13, 20, and 25, respectively, because said nucleic acids could be incorporated into vectors that may be introduced into host cells that produce said caninized anti-PD-1 antibody for laboratory or clinical applications. The invention of the conflicting claims and Papadopoulos et al. meets the limitations of the instant claims 18-21 and 40.
Therefore the claimed invention is prima facie obvious to one of ordinary skill in the art over the conflicting claims in view of Papadopoulos et al.
35 U.S.C. 102(a)(1)
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.
Claim 20 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sasu et al. (US PG PUB 2008/0213277, publication date: 09/04/2008).
At [0096], Sasu et al. teach SEQ ID NO: 27, which is a heavy chain variable region from the 2.7 antibody. SEQ ID NO: 27 of Sasu et al. comprises the amino acid sequence GYTFTTYGMS, which shares 100% sequence homology with the instant SEQ ID NO: 27. At [0015], Sasu et al. teach nucleic acids that encode antibodies of the invention. As such Sasu et al. teach a nucleic acid that encodes the instant SEQ ID NO: 27, thus meeting the limitations of claim 20.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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