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 1-45 and 48-51 are cancelled.
Claims 46-47 are currently amended.
Claims 46-47 and 52-73 are pending and under examination on the merits.
Priority
This application is a DIV of U.S. Application Serial No. 17/710,243, filed March 31, 2022 and claims priority to NL 2027892, filed on March 31, 2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Objections and Rejections
Any and all objections and/or rejections of cancelled claims 1-45 and 48-51 are withdrawn as moot in light of cancellation of the claim(s). The rejection of claim 47 under 35 USC §112(b) is withdrawn in light of the clarifying claim amendments dated 12/17/2025.
Notice
Applicant has amended the claims via the amendments dated 12/17/2025 to recite SEQ ID NO: 27 where SEQ ID NOs: 42 or 45 had previously been recited (see for example, claim 46). This does not substantively alter the claim scope because SEQ ID NOs: 27, 42, and 45 have the exact same sequence (100% identity), as verified by sequential alignment.
Maintained Claim Rejections Except for Alterations Accounting for Newly Added Claims or Altered Claim Scope Resulting from the Claim Amendments
35 U.S.C.112(a)
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.
Written Description
Claims 46-47 remain rejected and newly added claims 52-57 are rejected under 35 U.S.C section 112(a) for failing to fulfill the written description requirement.
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. Dianwnd 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. This is a written description rejection.
The claims recite a genus of anti-PD-1 antibodies allowing for mutations within the CDRs and/or interchangeability of the pairing of a single set of HCDRs with a single set of LCDRs (where the 3 HCDRs and 3 LCDRs form the set of 6 CDRs of the binding site). It is well-known in the art that specificity of an antibody stems from the interaction of six CDRs and CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies (HCDRS may not be arbitrarily paired with LCDRs with a reasonable expectation of binding an envisioned antigen and vice a versa). For example, WO 2008068048 A2 discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 A1 describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no evidence in the instant specification that a single CDR placed in the context of two to five other CDRS from a different antibody would result in the required function, nor that a single chain is correlated to the required function when combined with any other arbitrary/interchangeable chain. As such, the specification fails to set forth a structure-function correlation sufficient to describe all possible antibodies with the permitted degree of mutation within the CDRs and interchangeability of the light chain CDRs (LCDRs).
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, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind PD-1. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). See additionally for example, McCarthy et al (J. Immunol. Methods, 251(1-2): 137-149, 2001; as cited on the 04/03/2024 IDS and further supported by the references cited, below), which demonstrated that a single VH CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind PD-1, as claimed.
Moreover, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Therefore, the general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of heavy and light chain CDR amino acid sequences, that correlate with the ability to bind PD-1, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The specification discloses certain specific antibodies (see pages 33-41), which represent 8 antibodies (see Figure 2 and Table 1). However, as discussed above, without any way to envisage which members of the genus would function as claimed, there is no way to determine if these antibodies represent the full breadth of what is claimed. Importantly, these disclosed species are structurally distinct and not representative of multiple species within the genus of claimed anti-human PD-1 binding antibodies. The disclosure of the specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
The specification does not describe which amino acid residues of the administered antibody are responsible for the functions claimed. Rather, the specification states that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides a few examples of potential generic agents, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant agents and fails to disclose which regions of the agents are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonably representative number of members of the genus of antibodies that bind PD-1 and have the permitted degree of mutations in the CDRs (as many as 2 mutations in each CDR are permitted; where certain claims further allow for interchangeability of the LCDRs), but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly 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 is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116)
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
However, in view of this disclosure, Applicant is claiming a broad genus of binding domains that would be expected to encompass multiple antigen-binding sites (sets of 6 CDRs) having diverse heavy and light chain CDR sequences. The specification does not provide adequate written description for the entire claimed genus, because in the absence of empirical determination, 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 heavy chain CDR sequences encompassed by the genus of substitutable antibodies comprising a VH having up to 2 amino acid substitutions per HCDR (up to 6 total substitutions per HCDR1-3 set) with an arbitrary light chain or LCDRs having up to 2 amino acid substitutions per LCDR (up to 6 total substitutions per LCDR1-3 set) would retain the ability to bind PD-1. As detailed below Applicant's disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant's disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
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. 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 species having 100% identity to the claimed VH and HCDR1-3 sequences along with 5 potential light chains having 100% identity to LCDR1-3 sequences. However, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of one 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 amino acid sequences that confer upon an antibody the ability to bind PD-1, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind PD-1. Absent a clear description of the at least minimal structural features correlating with a functional ability to function as claimed 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 CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to bind PD-1, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision.
Therefore, the enumerated instant claims 46-47 and 52-57, as presently drafted, are not held to have met the written description requirement of 35 USC 112(a).
Enablement
Claims 46-47 remain rejected and newly added claims 52-73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a blood, skin, lung, liver, bladder and kidney cancers cancer does not reasonably provide enablement for treating all cancers or the breadth of the genus of cancers presently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
The claims are broadly directed to a method for treating a disease wherein certain dependent claims narrow the disease to cancer (beginning with dependent claim 58). The only active step of recited in the claims is administering an effective amount of an anti-human PD-1 binding domain or a pharmaceutical composition thereof.
The nature of the invention
The claims are broadly directed to a method for treating a disease wherein certain dependent claims narrow the disease to cancer (beginning with dependent claim 58). The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that cancer is a highly heterogenous disease (as evidenced by Allison et al, Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014); at paragraph 1 of the Introduction) and there is no reasonable expectation to expect an anti-PD-1 antibody to treat all diseases or even all cancers as there is there no single/universal (one) cure for cancer (as evidenced by American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be-cured.html) (2021)).
The level of one of ordinary skill
As the claims are directed treatment of disease, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
As discussed above, Allison et al and American Cancer Society teach the heterogeneity of cancers and their treatments and demonstrate that the characterization, pathology, and treatment of different cancers are unpredictable.
Additionally, He et al (Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020 Aug;30(8):660-669. doi: 10.1038/s41422-020-0343-4) teach that the most successful immune checkpoint blockade therapy is anti-PD-1/PD-L1 therapy that has been approved to treat a wide variety of cancer types. However, the major bottleneck of immune checkpoint blockade therapy is its low response rate in most cancers, with a range of 10%–30%. For some major cancer types such as colorectal cancer with microsatellite stability, anti-PD-1/PD-L1 therapy shows nearly no effect (see He et al’s Introduction). There is no evidence of record that supports the idea that targeting PD-1 would be effective for all diseases or even all cancers.
(F) The amount of direction provided by the inventor
The specification provides no exemplary or enabling guidance enabling treatment of all diseases or even all cancers.
The existence of working examples
The specification provides no exemplary or enabling examples.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There are no working example provided and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention in its full scope, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph. Therefore, only a method for treating blood, skin, lung, liver, bladder and kidney cancers (See He et al’s Introduction) is viewed to be enabled at this time.
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 46-47, 52-56, and 61-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/708,901 (reference application).
Regarding claims 46-47 and 52, the reference application recites an anti-PD-1 antibody having identical CDRs to the anti-PD-1 antibody of the instant Application. Reference SEQ ID NO: 7 comprises instant CDR SEQ ID NOs: 43-44-27. Reference SEQ ID NO: 6 comprises instant CDR SEQ ID NOs: 40-41-27 and 43-44-27. Reference SEQ ID NO: 5 comprises instant CDR SEQ ID NOs: 37-38-39. Reference SEQ ID NO: 4 comprises instant CDR SEQ ID NOs: 34-35-36. Reference SEQ ID NO: 3 comprises instant CDR SEQ ID NOs: 31-32-33. Reference SEQ ID NO: 2 comprises instant CDR SEQ ID NOs: 28-29-30. Reference SEQ ID NO: 1 comprises instant CDR SEQ ID NOs: 25-26-27 (see reference claims 17 and 52-65). Reference SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1. Reference SEQ ID NO: 2 is 100% identical to the instant SEQ ID NO: 2. Reference SEQ ID NO: 3 is 100% identical to the instant SEQ ID NO: 3. Reference SEQ ID NO: 4 is 100% identical to the instant SEQ ID NO: 4. Reference SEQ ID NO: 5 is 100% identical to the instant SEQ ID NO: 5. Reference SEQ ID NO: 6 is 100% identical to the instant SEQ ID NO: 6. Reference SEQ ID NO: 7 is 100% identical to the instant SEQ ID NO: 7 and is 93.3% identical to instant SEQ ID NO: 9 (see reference claims 17 and 52-65). The inclusion of the PD-1 binding moiety in a bivalent IgG format, absent evidence to the contrary, would not have been understood to alter measured binding affinity between the moiety and the PD-1 such that said modification would have been a functionally equivalent, obvious variant as presently claimed. Because the claims of the reference application disclose the same structure that is required by the instant claims, the co-pending (reference) claims are held to make obvious the instant claims because function inherently flows from structure so the binding and function would presumably be the same.
The copending reference application claims does not appear to explicitly provide motivation to use the claimed antibody to treat disease.
However, the specification can be used to determine the utility of a product. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1385 (CAFC 2010) (“Our prior obviousness-type double patenting decisions in Geneva and Pfizer … we found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent”). See also MPEP § 804(II)(B)(2)(a).
The specification of the copending reference application teaches that an object of its disclosure is to provide new agents for treatment of human disease, in particular for the treatment of cancer (see for example page 2, lines 19-20; page 3, lines 14-19; and page 40, lines 21-24).
Therefore, the artisan would have found it obvious to use the binding moiety comprising the instantly claimed sequences (alone, as a fragment, or as a bispecific/multispecific) to treat a human disease, such as cancer.
Regarding claims 53-54, the reference application claims the above noted HCDR combination/HCVR further comprising LCDR1-3 having SEQ ID NOs: 60, 61, and 62, respectively, where reference SEQ ID NO: 60 is 100% identical to instant SEQ ID NO: 49, reference SEQ ID NO: 61 is 100% identical to instant SEQ ID NO: 50, and reference SEQ ID NO: 62 is 100% identical to instant SEQ ID NO: 51 (see for example, reference claim 51).
Regarding claims 55-56, the reference application claims the instantly recited HCDR combinations further comprising an LCVR having SEQ ID NO: 24, where reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 (see for example, reference claim 47).
Regarding claim 61, the reference application claims a PD-1 binding domain having an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 24 (where reference SEQ IS NOs: 1 and 24 are 100% identical to instant SEQ ID NOs: 1 and 16, respectively) (see for example, reference claim 52).
Regarding claims 62-63, as discussed above, the reference application claims a PD-1 binding domain where the HCVR comprises one of SEQ ID NOs: 1-8 and an LCVR that comprises SEQ ID NO: 24, where reference SEQ ID NO: 2 comprises instant CDR SEQ ID NOs: 28-29-30 and reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 and comprises LCDR1-3 having amino acid sequences identical to instant SEQ ID NOs: 49, 50, and 51, respectively (see for example, reference claim 15).
Regarding claims 64-65, as discussed above, the reference application claims a PD-1 binding domain where the HCVR comprises one of SEQ ID NOs: 1-8 and an LCVR that comprises SEQ ID NO: 24, where reference SEQ ID NO: 3 comprises instant CDR SEQ ID NOs: 31-32-33 and reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 and comprises LCDR1-3 having amino acid sequences identical to instant SEQ ID NOs: 49, 50, and 51, respectively (see for example, reference claim 15).
Regarding claims 66-67, as discussed above, the reference application claims a PD-1 binding domain where the HCVR comprises one of SEQ ID NOs: 1-8 and an LCVR that comprises SEQ ID NO: 24, where reference SEQ ID NO: 4 comprises instant CDR SEQ ID NOs: 34-35-36 and reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 and comprises LCDR1-3 having amino acid sequences identical to instant SEQ ID NOs: 49, 50, and 51, respectively (see for example, reference claim 15).
Regarding claims 68-69, as discussed above, the reference application claims a PD-1 binding domain where the HCVR comprises one of SEQ ID NOs: 1-8 and an LCVR that comprises SEQ ID NO: 24, where reference SEQ ID NO: 5 comprises instant CDR SEQ ID NOs: 37-38-39 and reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 and comprises LCDR1-3 having amino acid sequences identical to instant SEQ ID NOs: 49, 50, and 51, respectively (see for example, reference claim 15).
Regarding claims 70-71, as discussed above, the reference application claims a PD-1 binding domain where the HCVR comprises one of SEQ ID NOs: 1-8 and an LCVR that comprises SEQ ID NO: 24, where reference SEQ ID NO: 6 comprises instant CDR SEQ ID NOs: 40-41-27 and reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 and comprises LCDR1-3 having amino acid sequences identical to instant SEQ ID NOs: 49, 50, and 51, respectively (see for example, reference claim 15).
Regarding claims 72-73, as discussed above, the reference application claims a PD-1 binding domain where the HCVR comprises one of SEQ ID NOs: 1-8 and an LCVR that comprises SEQ ID NO: 24, where reference SEQ ID NO: 6 comprises instant CDR SEQ ID NOs: 40-41-27 and 43-44-27 and reference SEQ ID NO: 24 is 100% identical to instant SEQ ID NO: 16 and comprises LCDR1-3 having amino acid sequences identical to instant SEQ ID NOs: 49, 50, and 51, respectively (see for example, reference claim 15).
Claim 57 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/708,901 (reference application) in further view of Janeway et al (The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The structure of a typical antibody molecule. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27144/).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 57, as discussed above, the reference application claims a PD-1 binding domain meeting the limitations of instant claim 56.
The reference application does not explicitly recite that the PD-1 binding domain comprises a CH1 and CL region.
However, Janeway et al, teaching the structure of a typical antibody molecule, teach that the typical antibody (a binding domain) comprises a CH1 and a CL region (see for example, the title of the Janeway reference and Figure 3.1 (paying particular attention to part b)) at page 1/6).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the reference Application and Janeway et al. The artisan would have been motivated to make and use the invention as claimed because Janeway et al teach the typical generic structure of an antibody which the artisan would find to be an obvious format to use with the structures of the reference application to facilitate therapeutic PD-1 binding. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
A. Applicant argues from withdrawal of the rejections for lack of written description stating that the Examiner fails to articulate a clear basis for rejection of the claims.
Response: The Examiner cited multiple references pertaining to the state of the art which demonstrate that the set of 6 CDRs must be specified because the binding site is formed by the interaction of the 6 CDRS where even a single mutation can alter binding. The Examiner further explained that the 8 antibodies disclosed is insufficient to provide a representative number of species or a structure-function correlation which would adequately describe the claimed genus of PD-1 binding domains. Further, it does not matter that Applicant claims that the binding domains must bind PD-1 because this does nothing to allow the artisan to envisage the genus of antibodies which would actually function to bind PD-1. While the claims do require some structure, the permitted degree of variation renders the required structure insufficient to comply with the written description requirement of 35 USC §112(a). This line of argument is unpersuasive and the rejections are maintained at this time.
B. Applicant argues for withdrawal of the rejections of the claims for lack of enablement because absent evidence to the contrary, the artisan would expect that the PD-1 binding domains could be put to the same use of treating disease.
Response: The Examiner cites references to show that the state of the prior art does not step in to provide enablement where the instant disclosure fails to do so. Applicant does not mention or account for these references in the remarks dated 12/17/2025. Applicant provides no evidenced showing of enablement. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). This is unpersuasive and the rejections are maintained at this time.
C. Applicant argues for withdrawal of the rejections for double patenting alleging an improper application of Sun Pharmaceutical Industries v. Eli Lilly Co and because the reference application is directed to a binding moiety that also binds LAG-3.
Response: Applicant states that Sun Pharmaceuticals v. Eli Lilly Co does not apply because, in that case, the compound of the reference application and the instant application are not identical. The Examiner disagrees. The instant claims recite an effective amount of compound that comprises the recited amino acid sequence structure. Comprising is intentionally open language allowing for more structure than what is explicitly recited in the claim such that the broadest reasonable interpretation of the instantly claimed binding domain does not preclude the additional structure(s) (responsible for LAG3-binding) which are claimed in the reference Application. Therefore, the Sun Pharmaceuticals v. Eli Lilly Co would appear to apply and the fact that the reference application comprises structure for binding LAG-3 does not obviate the clear and obvious overlapping scope of the reference claims relative to the instant claims. Therefore, the rejections are maintained at this time.
Conclusion
No claim is allowed.
As noted in the office action dated 09/17/2025, the sequences having 100% identify (no substitutions) to the HCDR combinations recited in claim 46 have been searched and are deemed to be free from the prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ono Pharmaceutical Co., Ltd., hereinafter ‘Ono’, (WO2006121168A1; as cited on the 04/03/2024 IDS) teaches an anti-PD-1 antibody comprising an HCVR and LCVR comprising sequences which are 100% homologous to instant SEQ ID NOs: 20 and 21, respectively (see Ono at claim 8, SEQ ID NOs: 4 and 11, respectively; see also Ono at page 3). Ono teaches that this antibody binds human PD-1 with an affinity of 1X10^-7M K.sub.D or less, with a preferred embodiment binding human PD-1 with an affinity of 1X10^-7M K.sub.D or less (see pages 2-3 of Ono).
Crescendo Biologics Ltd., hereinafter CBL, (US 20190322749 A1; as cited on the 04/03/2024 IDS) CBL teaches an anti-PD-1 VH with a biasing affinity for human PD-1 of 7.82X10^-11 K.sub.D M (See row 1 of table 13). Note that this is a 10 fold greater affinity for human-PD-1 than is explicitly recited by the reference antibody as taught by Ono, as discussed and cited, above. CBL further teaches that, “[b]inding kinetics of certain humabodies [VH, trademark of Crescendo Biologics Ltd] binding to human PD-1-hu Fc were measured by surface plasmon resonance (SPR) technology using Biacore T200 instrument (GE Healthcare),” (see paragraphs 0402-0403). CBL teaches methods of administering this antibody to treat cancer and disease (neurological disease; see claims 33, 34, and 36-37 of CBL). CBL teaches an embodiment, the 1.1a Humabody VH of Table 15, which has a binding affinity for human PD-1 of 6.76X10^-10, which is 0.676nM. CBL teaches that, “In another aspect of the present invention, there is provided a pharmaceutical composition comprising a binding agent or composition according to the present invention and optionally a pharmaceutically acceptable carrier,” (see paragraph 0259).
Bernett (US 20180127501 A1; as cited on the 04/03/2024 IDS) teaches a bispecific antibody that binds PD-1 (see claims 1, 3, 5-6, and 15). Bernett further teaches that:
“Specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10−4 M, at least about 10−5 M, at least about 10−6 M, at least about 10−7 M, at least about 10−8 M, at least about 10−9 M, alternatively at least about 10−10 M, at least about 10−11 Mat least about 10−12 M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction,”
(see paragraph 0189). Note that this is a 10 fold increase in affinity as compared to that of Nivolumab as taught by Ono, as discussed above. Bernett further teaches:
“ In further aspects, the invention provides heterodimeric antibodies comprising: a) a first heavy chain comprising a first Fc domain, an optional domain linker and a first antigen binding domain comprising an scFv that binds a first antigen; b) a second heavy chain comprising a heavy chain comprising a heavy chain constant domain comprising a second Fc domain, a hinge domain, a CH1 domain [teaching a CH1 region] and a variable heavy domain; and c) a light chain comprising a variable light domain and a light chain constant domain [teaching a CL region]; wherein said variable heavy domain and said variable light domain form a second antigen binding domain that binds a second antigen, wherein one of said first and second antigen binding domains binds human ICOS and the other binds human PD-1,”
(see paragraph 0012).
Fessas et al (A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol. 2017 Apr;44(2):136-140. doi: 10.1053/j.seminoncol.2017.06.002; as cited on the 04/03/2024 IDS) teaches that:
“Crystal structures of the PD-1 ectodomain in complex with the Fab fragments of nivolumab and pembrolizumab have shown that there is a significant overlap between the epitopes of both of these mAbs with the PD-L1 binding site. Nivolumab binds PD-1 by using the N-terminal extension, FG and BC loops as a platform for binding. The binding affinity is heavily dependent on the N terminal extension, which is not involved in PD-L1 recognition, while the overlapping binding surface shared by the VL region of the antibody and PD-L1 resides mostly on the FG loop. On the other hand, the interaction of pembrolizumab with PD-1 is heavily dependent on the flexible C′D loop of PD-1, which is not involved in the interaction with PD-L1. However, its interaction also with the C and C′ strands of PD-1 ensure that it competes with the binding of PD-L1. In addition, binding of either of these antibodies induces small conformational changes in the flexible BC and FG loops of PD-1, which are incompatible with PD-L1 binding. These structural features suggest that both these antibodies have a similar mechanism of action whereby they competitively inhibit PD-L1 binding by direct occupancy and steric blockade of the PD-L1 binding site,”
(see paragraph 2 of section 3).
Geuijen (US 20200325227 A1; as cited on the 04/03/2024 IDS) teaches, that “bivalent monospecific antibodies that comprise two of said variable domains that bind PD-1, and bivalent monospecific antibodies that comprise two of said variable domains that bind PD-L1,” are known in the art and discloses that their invention was compared to such bivalent, monospecific antibodies. Geuijen further teaches that:
“In some embodiments, an antibody of the invention is an IgG, preferably a full length IgG. Full length IgG antibodies are preferred because of their typically favorable half-life and the desire to stay as close to fully autologous (human) molecules for reasons of immunogenicity. In some embodiments, an antibody of the invention is a full length IgG1, a full length IgG2, a full length IgG3 or a full length IgG4 antibody,”
(see paragraph 0268).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678