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 .
Election/Restrictions
Applicant's election with traverse of antibody 43586p1.2.F06 comprising a heavy chain of Seq ID No: 19 and a light chain of Seq ID No: 73 in the reply filed on 10/08/2025 is acknowledged. The traversal is on the ground(s) that it is not a search burden to search all combinations of CDRs set forth in Figure 1 and 2. This is not found persuasive because figures 1 and 2 includes over 50 antibody heavy/light chain variable regions (VH/VL). The language of claim 1 encompasses up to 10 amino acid substitutions in the collective CDR regions of the variable domain of (a); and therefore, an exponential multitude of antibodies which is a search burden.
The requirement is still deemed proper and is therefore made FINAL.
Status of the Claims
Claims 1-21 were originally filed 9 January 2023 and the preliminary amendment filed the same day has been entered. Claims 1-21 are currently pending and under consideration.
Claim Interpretation
For the purposes of applying prior art, the claim scope has been interpreted as set forth below
per the guidance set forth in MPEP § 2111. If Applicant disputes any interpretation set forth below,
Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in
the subsequent response to the instant action. Applicant is advised that a specialized definition should
be properly supported and specifically identified (see, e.g., MPEP § 2111.01 (IV), describing how Applicant may act as their own lexicographer).
Claim 17 is drawn to a method of treating cancer comprising administering to a cancer patient an effective amount of an antibody. The specification defines “a method of treating cancer” as encompassing prophylactic treatment in terms of completely or partially preventing a disease (see specification pg. 6 lines 21-23, pg. 34 lines 3-4). In particular the specification discloses, “covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it” (see specification pg. 6 lines 23-26). Given the method of treating cancer is intended to encompass preventing cancer the recitation of a cancer patient is understood to encompass patients who are predisposed to cancer (e.g., genetically) and may not yet have a cancer diagnosis.
Claim Objections
Claims 18 and 20 are objected to because of the following informalities:
Claims 18 and 20 recite “wherein the patient” in line 1 and should recite, “wherein the cancer patient” for consistency.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
Claims 1, 2, and 4-21 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 i. an anti-TIGIT antibody comprising a particular set of VH and VL sequences (see claims 1 and 2), does not reasonably provide enablement for anti-TIGIT antibodies comprising i. any 3 heavy chain complementarity determining regions (HCDRs) paired with any 3 light chain complementarity determining regions (LCDRs) (see claim 1a), ii. up to 10 amino acid substitutions in the CDR regions (see claim 1b), and iii. at least 90% sequence identity (see claim 2). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Additionally, claims 15-21 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As a preliminary matter please note the following:
“The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005) expressly recognized that the USPTO employs the ‘broadest reasonable interpretation’ standard:
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The Patent and Trademark Office (‘PTO’) determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must ‘conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description.’ 37 CFR 1.75(d)(1).” (see MPEP § 2111).
“All questions of enablement are evaluated against the claimed subject matter. The focus of the examination inquiry is whether everything within the scope of the claim is enabled. Accordingly, the first analytical step requires that the examiner determine exactly what subject matter is encompassed by the claims.”(emphasis added) (see MPEP § 2164.08).
Claim 1 (scope of enablement) is drawn to a genus of anti-TIGIT antibodies comprising any three HCDRs disclosed in figure 1 paired with any three LCDRs disclosed in figure 2 (i.e., approximately 50+ antibody VH/VL regions are disclosed in each figure) (see claim 1a) or alternatively any of claimed antibodies with up to 10 amino acid substitutions in the CDR regions (see claim 1b). Given the 35 USC 112(b) rejection (see below) regarding the indefiniteness of the CDRs Applicant is enabled for a particular corresponding pair of full length VH and VL regions. Instant claim 1 encompasses a large genus of anti-TIGIT antibodies with variable CDRs in various VH and VL combinations using various CDR numbering schemes (see specification pg. 5 lines 18-27 and Table 1).
Claim 2 (scope of enablement) is drawn to at least 90% sequence identity to any pair of VH and VL region selected from figures 1 and 2. In the case of instantly elected antibody 43586p1.2.F06, the language of claim 2 encompasses a genus of antibodies with up to 23 amino acid substitutions across both Seq ID Nos: 19 and 73 including CDR regions.
Claim 15 (not enabled) is drawn to “method for inhibiting TIGIT, comprising contacting a cell comprising TIGIT with an antibody of claim 1”.
Claim 16 (not enabled) is similarly drawn to a “method of inhibiting TIGIT in a subject, comprising administering to the subject an effective amount of the antibody of claim 1”.
These claims given their broadest reasonable interpretation consistent with the teachings of the instant specification and knowledge in the prior art would be understood by the ordinary skilled artisan to read on a method that could be practiced in vitro or in vivo.
Claims 17-19 (not enabled) are method claims drawn to methods of treating cancers/species of cancer comprising administering to a cancer subject the genus of antibodies encompassed in claim 1. It is noted the specification includes within the definition of treating “prevented from happening, or stopped” and therefore a method of treating cancer encompasses prevention of any cancer is a subject which has not yet been diagnosed with cancer (see claim interpretation above; see specification pg. 35 lines 3-4).
The specification discloses TIGIT is a co-inhibitory receptor protein that limits T cell proliferation and activation. TIGIT competes with CD226 for binding to CD155 wherein TIGIT has preferential binding thereby inhibiting CD226 signaling and limiting T cell proliferation and activation (see specification pg. 1 lines 9-16). Previous work in animal models has shown blockade of both PD-L1 and TIGIT has synergistic enhancement of CD8+ T cells mediated tumor rejection while other work has suggested TIGIT blockade is only effective in the presence of the co-activating receptor CD226 (see specification pg. 1 lines 27-33). The instantly disclosed antibodies bind to TIGIT while a subset inhibit TIGIT/CD155 interactions (see specification pg. 2 lines 6-8). From Applicant’s disclosure the ordinary artisan would understand TIGIT is found on several subsets of T cells, such as activated, memory, and regulatory T cells and natural killer (NK) cells (see specification pg. 1 lines 10-11), functions through multiple signaling pathways (e.g., CD155 and CD112) and competes with other receptors (e.g., CD226) for binding. Given the various mechanisms of action of TIGIT and the potential requirement of a co-activating receptor the ordinary artisan would understand the beneficial therapeutic effects of binding to TIGIT may be epitope specific and require additional elements.
The specification discloses the treatment methods are directed to cancer as a monotherapy or in combination (see specification pg. 3 line 20). The specification particularly names a limited number of cancers (see specification pg. 36, last para) although it is noted the named cancers are not set forth in a limiting manner. It is noted the specification does disclose a broader genus of treating “disease” however does not specify any particular class or species of disease beyond cancer (see specification pg. 6 line 20-27).
For example, “covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease” (see specification pg. 6 lines 20-27).
Inhibition of TIGIT (see claims 15-17) is disclosed in the context of treating cancer by inhibiting one of multiple binding interactions (i.e., TIGIT/CD155) in order to inhibit the immune-mediated eradication by inhibiting anti-tumor responses of T and NK cells (see specification pg. 1, 3rd para). Thus, regarding the in vivo methods of claims 15 and 16 the utility of the claimed methods “inhibiting TIGIT in a subject” would be understood by the skilled artisan to lie in treating a particular disease associated with said target cell expressing TIGIT, i.e., certain cancers, in a subject in need thereof. By contrast the skilled artisan knowledgeable of the prior art and the teachings of the instant specification would not be interested in “inhibiting TIGIT” in any given subject merely for the sake of doing so.
Put another way, based on the teachings of the instant specification it would not be clear to the skilled artisan in what context other than treating a subject suffering from cancer associated with said TIGIT/CD155 interactions would the skilled artisan wish to inhibit TIGIT/CD155 interactions in any given subject.
Thus, even if the claims do not explicitly recite, “a method of treating non-small cell lung cancer and melanoma comprising administering a particular anti-TIGIT antibody” the skilled artisan would understand claims 15 and 16, insofar as they will be practiced in vivo, to be directed towards methods that are to be practiced in the context of treating cancer as recited in instant claim 17.
That established, when the teachings of the instant specification are considered in the context of the knowledge in the prior art the skilled artisan is not enable to practice the breadth of the claimed invention in the absence of undue experimentation.
Applicants isolated 50+ anti-TIGIT antibodies from immunized human TIGIT-Fc OMNICHICKEN™ transgenic chickens comprising particular sets of VH and VL pairs (see specification pg. 37 lines 15-18; see figures 1-2). However, not all of the isolated antibodies bind human, cynomolgus monkey, and murine TIGIT nor do they all block TIGIT/CD155 interactions (see specification pgs. 39-43, Tables 3-5). For example, while antibodies 43586p2.B02, 43586p2.B05, and 43586p2.C01 bind only human TIGIT (i.e., not cynomolgus monkeys or murine) they do not inhibit the TIGIT/CD155 interactions (see specification pg. 41 table 4, pg. 43 Table 5). Therefore, an ordinary artisan would understand that binding to TIGIT is not sufficient to confer inhibition of TIGIT/CD155 interactions (i.e., inhibition of TIGIT in a cell/subject or method of treating cancer, claims 15-19). Furthermore, Applicant discloses not all of the claimed antibodies bind to TIGIT (e.g., antibody 43586p1.2.A4) (see specification pg. 41 table 4, pg. 42, Table 5). Applicant has not provided a working example of the claimed antibodies in a method of inhibiting TIGIT in a subject nor a method of treating cancer. Applicant’s working example of inhibiting TIGIT by contacting a cell comprising TIGIT with an antibody is limited to the in vitro environment and specifically blocking CD155/TIGIT signaling (i.e., a limited scope of TIGIT function). Thus, the ordinary artisan would understand from Applicant’s working example that i. not every combination of the disclosed CDRs may result in an antibody that binds to TIGIT, let alone those with up to ten amino acid substitutions nor any pairing of any VH from figure 1 with any VL from figure 2, and ii. binding to TIGIT is not sufficient to confer inhibition of TIGIT/CD155 interactions, nor does it inform the outcome of TIGIT’s interactions with other binding partners.
State of the Art
Regarding variable CDRs (see claims 1 and 2), the state of the art teaches CDR sequences are the residues required for antigen binding and these sequences are highly variable in order to facilitate binding to a multitude of antigens (see Kapingidza et al. 2020. Antigen-Antibody Complexes. Vertebrate and Invertebrate Respiratory Proteins, Lipoproteins and other Body Fluid, CH 19, pgs. 465-484, pg. 468, lines 1-4). Culang also teaches CDRs are widely assumed to be responsible for antigen recognition (see Culang et al. The structural basis of antibody-antigen recognition. Front. In Immun. 2013. Vol. 4, Article 302, abstract). The mutation effects at interfaces are often unpredictable and more often than not result in decreased binding affinity (see Clark et al. Influence of canonical structure determining residues on antibody affinity and stability. Journal of Structural Biology 185 (2014) 223–227, pg. 223, 2nd col. 1st full para). Amino acids within the CDR regions can also have cooperative effects. For example, substitutions in the AQC2 antibody of M32L in LCDR1 when paired with a conservative substitution Y70F retains nearly wildtype affinity compared to pairing with V29I which resulted in a near complete loss of binding affinity. In another example, a M32I substitution parried with A25F resulted in total loss of binding (see Clark, Table 1, pg. 223, 2nd col. 1st full para). Similarly, Brown demonstrated using single mutations in a T15 antiphosphocholine Ab leads to a loss in antigen binding in 1 of 15 antibodies while 2-4 mutations saw 16 of 31 antibodies lose antigen binding (see Brown et al. Tolerance to Single, but Not Multiple, Amino Acid Replacements in Antibody VH, CDR2. J Immunol (1996) 156 (9): 3285–3291.pg. 3285, 1st col. 1st para, Table 1, pg. 3290 1st col. last para). A person of ordinary skill in the art would understand that substitutions in CDR regions can result in a complete loss of binding for the target.
Regarding preventing cancer as encompassed by claims 17, the state of the art teaches that to date preventing cancer has yet to be obtained. For example, preventing gastric cancer is primarily directed to life style modifications such as diet, exercise, and smoking cessation to reduce the incidence of gastric cancers (see Rawla and Barsouk. Epidemiology of gastric cancer: global trends, risk factors and prevention. Gastroenterology Rev 2019; 14 (1): 26-38, pg. 26, 2nd col. 1st para). Yet, despite being one of the most behaviorally influenced, and thus preventable cancers, gastric cancer was the 5th most commonly diagnosed and the 3rd most deadly (see Rawla pg. 26, 2nd col. 1st para, pg. 35, 2nd col. last para). A person of ordinary skill would recognize that prevention of any cancer has yet to be achieved.
Regarding treating any cancer or administering to any subject any anti-TIGIT antibody the state of the art at the time of filing teaches i. TIGIT functions through multiple signaling pathway, ii. is expressed on several types including healthy subjects, iii. anti-TIGIT cancer therapies have been abandoned for toxicity and lack of efficacy in humans, and iv. transitioning from preclinical models to humans is highly unpredictable.
In particular, Chauvin and Zarour disclose TIGIT,
“plays a critical role in limiting adaptive and innate immunity. TIGIT participates in a complex regulatory network involving multiple inhibitory receptors (IRs) (e.g., CD96/TACTILE, CD112R/PVRIG), one competing costimulatory receptor (DNAM-1/CD226), and multiple ligands (e.g., CD155 (PVR/NECL-5), CD112 (Nectin-2/ PVRL2))” (see Chauvin and Zarour (2020) TIGIT in cancer immunotherapy. J for ImmunoTherapy of Cancer; 8, e000957, pg. 1, 2nd col. 2nd para, figure 1).
The implications of these other binding partners/signaling pathways in cancer therapy at the time of filing had yet to be determined,
“one has to keep in mind that the role of CD96 as an IR remains controversial. Further, evidence that CD112R blockade can potently enhance autologous human tumor antigen-specific CD8+ T cells is still missing.” (see Chauvin and Zarour pg. 6, 1st col. 3rd para).
The state of the art also teaches,
“In addition, CD226 plays a critical role as a master regulator of dual PD-1/TIGIT blockade. Its downregulation by CD8+ T cells and NK cells in the TME may represent a major obstacle for the success of dual PD-1/TIGIT blockade in the clinic” (see Chauvin and Zarour pg. 6, sentence spanning cols 1-2).
TIGIT is highly expressed by Tregs in peripheral blood mononuclear cells of healthy donors, patients with cancer, and in the tumor microenvironment (TME) (see Chauvin and Zarour pg. 1, 2nd col. 3rd para). Specific expression of TIGIT has been found on activated CD8+ and CD4+ T cells, NK cells, regulatory T cells, and follicular T helper cells in humans and weakly expressed in naïve T cells (see Chauvin and Zarour pg. 1, 2nd col. 3rd para). Five years post filing teaches several major pharmaceutical companies including Roche and BeiGene have abandoned anti-TIGIT cancer therapy (see Cui et al. (2025) TIGIT in cancer: from mechanism of action to promising immunotherapeutic strategies. Cell Death and Disease 16:664, in particular pg. 8, 2nd col. last para).
“Clinical trials of some mAbs that target TIGIT did not reproduce the promising preclinical data; in fact, administration of the anti-TIGIT mAbs alone often was associated with severe treatment-related adverse events (TAREs) and low objective response rate (ORR)” (see Cui pg. 2, 1st col. 1st para), and
“TIGIT expression levels in peripheral blood and tumor tissues in patients with primary breast cancer (PBC) seem to be related to the age of the patient, but not the tumor size or lymph node metastasis” (see Cui pg. 2, 1st col. 2nd para).
This is echoed by Qi who showed anti-TIGIT antibodies had no effect in a common preclinical assay for assessing/predicting therapeutic benefit of immune-oncology agents (see Qi et al. (2022) CBL-B inhibition showed differentiated effects in a mixed lymphocyte reaction versus other immune-oncology targeted approaches. J Immunother Cancer; 10(Suppl 2): A1-A1603, in particular pg. A1405 Results section). Cui suggests TIGIT is ineffective in some “cold” TME because it relies on the cytotoxicity of T/NK cells which are generally absent or insufficient in TME (see Cui pg. 9, 1st col. last para). The state of the art at the time of filing called for caution in targeting TIGIT in AML patients given overexpression of TIGIT in NK cells was associated with increased function contrasting the typically suppressive effects in CD8+ T cells (see Jia et al. (2018) TIGIT expression positively associates with NK cell function in AML patients. Blood 132(Supplemental 1):5250, last 2 para). Furthermore, an ordinary artisan would know anti-TIGIT antibodies in clinical trials for various combinations and indications to date have either failed (i.e., Roche, tiragolumab) or been discontinued (i.e., Bristol Myer Squibb, Merck, BeiGene, and GSK) due to unsatisfactory results (see Cui pg. 8, 1st col. 2nd full para). Specifically,
“The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing” (see Manallac (2025) Troubled TIGIT space. BioSpace, pg. 2, 2nd para), and
“Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer” (see Manallac para spanning pgs. 2-3).
Recent findings (i.e., 2025) indicate one possible reason anti-TIGIT antibodies hold promise in preclinical models but fail in human trials is TIGIT is shed in macaques but not humans in the presence of plasmin and therefore results in these preclinical studies “may yield misleading data on safety and efficacy” (see Drug Target Review (2025) Why TIGIT cancer therapies work in monkeys but not in humans. November 2025, pg. 3 purple highlighting, pg. 4, 4th para).
Accordingly, regarding claims 1, 2, and 4-21 and the scope of enablement the amount of experimentation required to develop the breadth of antibodies that bind to TIGIT with i. any 3 HCDRs from figure 1 and any 3 LCDRs from figure 2, ii. any pair of VH and VL sequences from figure 1 and 2, and iii. any antibody with up to 10 collective amino acid substitutions in the CDR regions is left to those skilled in the art. Further, experimentation required to subsequently identify those that not only bind TIGIT but also inhibit TIGIT activity (i.e., through any mechanisms) that can then be used to treat or prevent any cancer/disease is also left to those skilled in the art. The present claims and disclosure amounting to nothing more than an invitation to the skilled artisan to develop such embodiments. Given the resource- intensive nature of the required experimentation, the skilled artisan would reasonably conclude that such experimentation would be unnecessarily, and improperly, extensive and undue.
Regarding claims 15-21 the amount of experimentation the ordinary artisan would have to undertake to first identify the antibodies which bind and inhibit TIGIT, including those beyond inhibiting CD155 interactions, identify conditions/diseases in which inhibiting TIGIT is in any way effective, while balancing the unpredictability in safety concerns and efficacy when transitioning from in vitro to animal to human models would take undue trial and error experimentation to practice the inventions of claims 15-21.
Claims 1, 2, and 4-21 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 breadth of claims 1, 2, and 4-21 are set forth above.
Applicants isolated 50+ anti-TIGIT antibodies from immunized human TIGIT-Fc OMNICHICKEN™ transgenic chickens comprising particular sets of 6 CDRS, VH, and VL pairs (see specification pg. 37 lines 15-18; see figures 1-2). However, not all of the isolated antibodies bind human, cynomolgus monkey, and murine TIGIT nor do they all block TIGIT/CD155 interactions (see specification pgs. 39-43, Tables 3-5). For example, while antibodies 43586p2.B02, 43586p2.B05, and 43586p2.C01 bind only human TIGIT (i.e., not cynomolgus monkeys or murine) they do not inhibit the TIGIT/CD155 interactions (see specification pg. 41 table 4, pg. 43 Table 5). Therefore, an ordinary artisan would understand that binding to TIGIT is not sufficient to confer inhibition of TIGIT/CD155 interactions (i.e., inhibition of TIGIT in a cell/subject or method of treating cancer, claims 15-19). It is noted, not all of the isolated antibodies appear to bind to TIGIT (e.g., antibody 43586p1.2.A4) (see specification pg. 41 table 4, pg. 42 Table 5). Applicant has not provided a working example of the claimed antibodies in a method of inhibiting TIGIT in a subject nor a method of treating cancer. Applicant’s working example of inhibiting TIGIT by contacting a cell comprising TIGIT with an antibody is limited to the in vitro environment and specifically blocking CD155/TIGIT signaling (i.e., a limited scope of TIGIT function).
There is no evidence from the disclosure that antibodies with i. any combination of 3 HCDRs and 3 LCDRs selected from figures 1 and 2, ii. any antibodies with any VH and VL pairing from figures 1 and 2, nor iii. any number of amino acid substitutions in any antibody selected from figures 1 and 2 were made. As stated above, the CDRs are integral for antigen binding (see above; Kapingidza pgs. 465-484, pg. 468, lines 1-4; see Culang abstract). Mutational effects on interfaces are often unpredictable(see Clark pg. 223, 2nd col. 1st full para). Therefore, a person of ordinary skill in the art at the time of filling would understand residues within the CDRs are integral to antigen binding or maintaining the structure of the region that binds to the antigen and substitutions in these regions would affect one or both these attributes. In addition, given TIGIT binding does not confer inhibition of TIGIT/CD155 interactions and there is no art-recognized correlation between structure and function, it would be impossible for one of ordinary skill in the art to predict which combination of CDRs, up to 10 amino acid substitutions in the CDRs, or pairs of VH and VL sequences would result in an antibody that i. binds to TIGIT, and/or ii. inhibits TIGIT, and/or iii. treats cancer. Furthermore, the ordinary artisan would understand the unpredictability in transitioning from preclinical models to human subjects when targeting TIGIT and lack of a working example of prevention of any cancer (see above). Therefore, the skilled artesian would have recognized Applicant was not in possession of the claimed invention at the time of filing.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-21 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.
Claims 1 and 2 are drawn to an antibody comprising CDRs1-3 identical to the CDRs1-3 of an antibody selected from Figure 1 and Figure 2. First, pursuant to MPEP §2173.05(s) 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).
In addition, it is unclear in claim 1 if the CDRs are limited to those in the boxes of Figure 1 and 2 or alternatively can encompass CDRs using alternative numbering methods (e.g., Kabat) as taught by the specification (see specification pg. 5, bottom).
Claim 1 also recites “wherein the antibody comprises: (a) a variable domain comprising: i. heavy chain… and ii. light chain” in lines 1-5. The scope of the antibody is unclear, the antibody comprises a (i.e., singular) variable domain but then specifies both heavy and light chains. Therefore it is unclear if the claimed antibody requires a singular domain or alternatively requires both the heavy and light chain as “and” in line 4 suggests.
Claim 1 also recites wherein “(b) a variant of said variable domain of (a) that is otherwise identical to said antibody variable domain except for up to 10 amino acid substitutions in the collective CDR regions of the variable domain of (a)” lines 7-9. The scope of the 10 amino acid substitutions is unclear. For example, is part b limited to up to 10 amino acids substitutions across the three CDR regions as part (a) refers to a singular variable domain or is part b intended to encompass up to 10 amino acid substitutions across both heavy and light chain variable domain.
Claim 2 is drawn to “at least 90% (e.g., at least 95%)” in lines 2-3 and 5-6. First the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Second, it is unclear if what is recited with the parentheticals is a limitation or alternative embodiment.
Claim 3 is drawn to “wherein the antibody selected from Fig. 2 is antibody 43586p1.2.F06 having a heavy chain of Seq ID NO: 19 and a light chain of Seq ID No: 73”. The scope of the antibody is unclear. First, claim 3 recites a heavy chain and light chain comprising Seq ID Nos: 19 and 73; however, these sequences are 120 and 110 amino acids long, respectively. Therefore, it is unclear if the antibody is drawn to comprising heavy and light chain variable regions as the sequence lengths would suggest, or alternatively, is the claim further limited to an antibody comprising a full length heavy and light chain as recited which comprises the claimed VH and VL sequences. Second, claim 3 is drawn to wherein the antibody selected from figure 2 is 43586p1.2.F06. It is unclear if the antibody is limited to comprising only the VL of 43586p1.2.F06 as that is what is set forth in Figure 2, paired with any VH (i.e., selected from Figure 1), or subsequently further modified to comprise up to 10 amino acid substitutions (claim 1(b)), or alternatively is claim 3 limited to an antibody comprising both claimed VH and VL sequences. Third, antibody 43586p1.2.F06 is indefinite. 43586p1.2.F06 is described in Figures 1 and 2 as comprising a particular VH and VL while also being described as a combination of particular CDRs. Therefore it is unclear what the meets and bounds of the antibody name 43586p1.2.F06.
Claims 4 and 5 recites the limitations "the heavy chain variable domain" and “the light chain variable domain” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 8 recites the limitation "the synthetic polymer" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 is drawn to an antibody comprising a heavy and light chain variable domain (i.e., two variable domains). Claim 1 from which claim 2 depends is drawn to a single variable domain. Therefore, claim 2 expands the scope of the number of variable domains recited in claim 1.
In addition, using the instantly elected antibody 43586p.1.2.F06 which comprises VH and VL sequences with 120 and 110 amino acids, respectively, the language of claim 2 would allow up to 12 substitutions in the VH and 11 substitutions in the VL. Therefore claim 2 expands the scope of the number of substitutions permitted in independent claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 1-2 and 4-21 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 1, 2, and 15-21 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Claims 1-2 are drawn to antibodies that bind TIGIT comprising 6 CDRs. It was well known in the art at the time of filing that the particular amino acid sequence of the antibody CDRs determine its structure (e.g., paratope). For example, during affinity maturation antibodies that bind the same structure but have unique CDRs also exhibit reduced flexibility (i.e., unique structure) (see Kaur and Salunke (2015) Antibody promiscuity: understanding the paradigm shift in antigen recognition. IUBMB Life, 67: 498-505, in particular pg. 499, 2nd col. 1st para, pg. 500, 1st col. last para). Specifically,
“However, CDRH3 in particular, has been shown to play a crucial role in antigen recognition in numerous studies. Its length as well as characteristic sequence motif are important determinants for antibodies responding to multiple epitopes. As a matter of fact, the H3 loop explores the entire conformational window to assume any geometry of the paratope unlike the other loops that assume a few canonical structures” (see Kaur and Salunke pg. 502, 2nd col. 1st para),
“It has been observed in various studies that germline antibodies harness malleability of the paratope topology including Cα and residue side-chain flexibility to accommodate different antigens while minimizing entropic penalty. Whereas the germline antibody BBE6.12H3 assumes distinct paratope topologies to accommodate independent synthetic peptide antigens, antibodies 36-65 and S25-2 do so by adopting a single paratope conformation and differentially juxtapositioning the epitopes, revealing spatially distinct signatures within the binding pocket” (see Kaur and Salunke pg. 502, 2nd col. last para), and
“On the other hand, the integration of the six CDRs together, each with its own unique amino-acid composition and contact preferences, could be the evolutionary response of the immune system that enables Abs to recognize virtually any surface patch on the Ag” (see Culang pg. 6 sentence spanning cols. 1-2).
Furthermore, Applicant’s own specification teaches not all the claimed antibodies bind TIGIT (e.g., 43586p1.2.A4, 43586p2.F10, 43645p1.F12), or have the same cross reactive profile (e.g., 43586p2.A03, 43586p2.B03, 43586p1.1.A7) (see specification Table 4 and 5). Therefore, the instantly claimed antibodies do not share a common structure (i.e., unique paratopes) nor a common function (i.e., binding TIGIT, or the same cross reactivity profiles). Regarding claims 15-21, Applicant’s disclosure demonstrates that binding to TIGIT is not sufficient for achieving functional inhibition of TIGIT/CD155 interactions (e.g., 43586p1.1.C2, 43586p1.2.A4, 43586p2.B03) (see specification Table 5).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claim allowed.
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/H.A.P./Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645