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 .
The Applicants’ Amendment to the Claims filed on August 15, 2025 is entered.
The Applicants’ Amendment to the Specification filed on August 15, 2025 is entered.
Claim status
Claims 2-33, 35, 37-59, 61-87, 89-90, 94-99, 101-103, 111-114, 117-122, and 124 are canceled.
Claims 1, 34, 36, 60, 88, 91-93, 100, 104-110, 115-116, and 123 are pending and under examination.
Priority
This US 17/811,513 filed on July 8, 2022 which is a CON of PCT/CN2021/070907 filed on 01/08/2021 claims Foreign priority benefit of CHINA PCTCN2020071336 filed on 01/10/2020. The Filing Receipt filed 11/14/2022 is considered as the most recent.
Information Disclosure Statement
The IDS filed on August 15, 2025 has been considered by the examiner. This IDS has checked the box indicating No IDS size fee is required under 37 CFR 1.17(v) at this time.
Response to Amendment
All objections and rejections made in the previous office action and not repeated in this office action are withdrawn.
Claim Rejections - 35 USC § 112 – maintained in part
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.
Claim 92 stands 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.
Claim 92 is indefinite because it recites “wherein the IgG4 Fc region comprises an S228P mutation” however the S228P mutation is not correlated to any sequence such as by a SEQ ID NO to define the amino acid position 228.
Response to argument
The applicants’ response filed on August 15, 2025 has been fully considered but is unpersuasive. The applicants argue that that the S228P mutation is a well-known term of art referring to a mutation of an amino acid residue shared by all wildtype IgG4 antibodies. The applicants argue:
First, one skilled in the art would recognize that Ser-228 is an amino acid residue present in the lgG4 core hinge, which is shared by all wildtype IgG4 antibodies, and that an S228P mutation can prevent Fab arm exchange (FAE) of IgG4 antibodies. For example, Crescioli, Silvia; et al., "IgG4 Characteristics and Functions in Cancer Immunity," Curr. Allergy Asthma. Rep., Vol. 16, No. 7, pp. 1-11 (2016) (“Crescioli,” cited in the Information Disclosure Statement submitted concurrently herewith), illustrates the Ser-228 residue in the core hinge of IgG4 in Fig. 1(a)(ii). Crescioli also states that the S228P mutation, “which renders the IgG4 core hinge more IgG1-like, abolishes the formation of intra-chain disulfide bond isomers and abrogates FAE in vitro and in vivo.” See Crescioli at page 4, second column, fourth full para. Furthermore, in Crescioli, the term “S228P mutation” was used as a well-known term of art without any definition of or reference to any specific antibody sequence. For example, Crescioli recites: “[t]herapeutic IgG4s carrying the S228P mutation are monospecific due to their inability to undergo FAE ... .” See Crescioli at page 8, second column, second full para. Accordingly, one skilled in the art would understand that an “S228P mutation” is a well- known term of art and would recognize and/or apply it in a claimed antibody without requiring reference to a specific sequence by a SEQ ID NO.
However, this argument is unpersuasive at least because it is not commensurate with the scope of the claims. Instant claim 92 depends from claim 91 which depends from claim 88, which depends from claim 1. Nothing in claims 1, 88, or 91 refers to a wild-type limitation or a wild-type sequence. Thus, the applicant is arguing features which are not recited in the present claims.
Scope of enablement
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.
Claims 1, 34, 36, 60, 88, 91-93, 100, 104-110, 115-116, and 123 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 a pharmaceutical and method of reducing a tumor in a murine colon cancer model using the specific antibody BsAb anti-TIGIT 2A3-Fc PD1-HCN version comprising instant SEQ ID NOs: 257 and 258, does not reasonably provide enablement for methods of treating and preventing any neoplasm in a subject using the scope of antibodies as 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 make and use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988)).
The nature of the invention: The instant claims are drawn to methods of treating and preventing neoplasms in a subject using multispecific antibodies comprising binding regions to TIGIT and PD-1 proteins. The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims: The claims are broad to antibodies and methods of using such for treating and preventing any type of neoplasm in a subject, including human subjects, using multispecific antibodies comprising binding regions to TIGIT and PD-1 proteins. The claims recite specific CDR sequences but the claims encompass 100 different bispecific antibodies, based on the combination of 25 anti-TIGIT binding moieties with 4 anti-PD-1 antibodies.
State of the Art: A review of the prior art patent and non-patent literature indicates that anti-TIGIT antibodies were known and effective to treat some cancers in a subject. Also, anti-PD1 antibodies were known and effective to treat some cancers in a subject. Also, bispecific antibodies using anti-TIGIT antibodies and an additional check-point inhibitor including PD1 inhibitors/antibodies are disclosed in the prior art. See Kon & Benhar (Drug Resistance Updates 2019 vol 45 pages 13-29; of record). Kon & Benhar explicitly suggest combining PD-1 inhibitors with TIGIT inhibitors and specify bispecific antibodies (see Abstract). However, the state of the art shows that the use of immune checkpoint inhibitor therapy, including the use of bispecific antibodies binding TIGIT and PD1, is considered to be unpredictable and any specific antibody must be tested to use for treating or preventing any type of neoplasms in a human subject. For example, Kon & Benhar disclose that many “patients receiving ICI therapy do not demonstrate a durable long-term response following ICI therapy”, and that “many patients receiving ICI therapy developing immune-related adverse events affecting a wide variety of organs” (Abstract).
Predicting which patients will benefit from this treatment is not a
simple task. Both PD-1/PD-L1 blockade as well as CTLA-4 inhibition are
considered more effective for cancers with higher tumor mutational
burden (TMB) (Diesendruck and Benhar, 2017; Popovic et al., 2018;
Saleh et al., 2019). However, a recent Phase III clinical trial failed to
demonstrate this correlation (Horn et al., 2018; Saleh et al., 2019).
Adding to this, CheckMate 214, a Phase III clinical trial assessing PD-1
and CTLA-4 inhibitory combination in renal cell carcinoma, failed to
demonstrate better survival outcome with PD-1/PD-L1 checkpoint inhibition therapy in PD-L1+ compared to PD-L1− patients (Labriola
et al., 2019; Motzer et al., 2018). Regarding efficacy, in a direct comparison between Nivolumab and Ipilimamab, Nivolumab outperforms
Ipilimumab (Eggermont et al., 2018).
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and the instant specification (discussed just below) and is not considered to provide sufficient enablement to practice the full scope of the claimed invention.
The predictability in the art: The nature of the presently claimed invention is unpredictable as evidenced by the Kon & Benhar reference discussed just above. Also, the instant specification shows that the embodiments of the presently claimed invention gave unpredictable results for in vitro binding assays using the four versions of bispecific TIGIT-PD1 antibodies reduced to practice in the specification. For example, see page 148, lines 4-7 which states:
TCR-mediated NFAT luciferase reporter activity was measured by a chemiluminescent plate reader. HCN version showed similar potency compared to parental anti-TIGIT 2A3-Fc, whereas all other three versions of BsAbs showed reduced potency compared to 2A3-Fc as shown in Figure 18.
Also, Table 4 shows that HCN version of the BsAb “demonstrated superior characteristics than other three versions”. Only this HCN version was used for the in vivo efficacy study.
The amount of guidance or direction needed to enable the invention is inversely related to the amount of predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). If the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). The instant specification provides many CDR sequences that may be used to make the claimed antibodies but only show four versions of such bispecific antibodies which are reduced to practice for performing binding assays in vitro. Figures 1-13 show cell assays using “representative bivalent antibodies in blocking TIGIT activity determined by luciferase reporter assays”. Figure 14 shows in vivo efficacy of the anti-TIGIT antibodies in a murine colon cancer model. Figure 15 “depict various structures of anti-TIGIT/anti-PD1 multispecific antibodies”. However, the structures shown in FIG 15 are general cartoon designs that do not indicate any specific CDR structure. Figure 16 shows binding affinity studies but does not indicate the CDR structures of the antibodies in these studies. Figures 17-21 depict whole cell binding assays and luciferase reporter assays. Figure 17 shows that BsAB HCN and LCN maintained binding affinity to h-TIGIT whereas HCC and LCC versions of BsAbs showed reduced binding affinity to h-TIGIT. The BsAbs shown are the versions called HCN, HCC, LCC, and LCN but no specific CDR structures are indicated.
Figure 22 shows an in vivo efficacy of BsAb in MC38 syngenic tumor model using h-PD1 and H-TIGIT double Knock-In C57BL/6 mice. Data from one BsAb is shown. Although FIG 22 does not describe which BsAb antibody structure was used, in the Brief Description of the Drawings of the specification it is stated that BsAb HCN was used.
Lastly, Figure 23 shows “multiple mechanisms of action of the anti-TIGIT/anti- PD1 antibodies”. Figure 23A shows a cartoon depiction that the BsAb can block inhibitory signals in PDI & TIGIT double or single positive CD8+ T cells and can block inhibitory signals from PDL1 & PVR double positive tumor cells or PVR single positive tumor cells. Figure 23B shows a cartoon depiction that “the BsAb can block inhibitory signal in NK cells and stimulatory signal in Tregs”. No BsAb structure is provided.
Working example: The specification shows no working example of a method of treating or preventing a neoplasm in a human subject. The specification shows one working example of a method of reducing a tumor in a murine colon cancer model using the specific antibody BsAb anti-TIGIT 2A3-Fc PD1-HCN version. The working embodiment in the instant application describes the construction of anti-TIGIT x anti-PD1 bispecific antibodies in Example 8. Four different versions were made using humanized, affinity matured anti-TIGIT clone 2A3 (aka VHH 2A3) conjugated to humanized, affinity matured anti-PD1 antibody “disclosed in PCT/US2017/050851” (published as WO2018/052818 A1). The specification states that structures of the BsAbs are shown in Fig 15 but these structures are general cartoon designs that do not indicate any specific CDR structure. As stated just above, Figure 22 shows an in vivo efficacy of BsAb in MC38 syngenic tumor model using h-PD1 and H-TIGIT double Knock-In C57BL/6 mice which is considered to be the only working example of the presently claimed invention. Data from one BsAb is shown. Although FIG 22 does not describe which BsAb antibody structure was used, in the Brief Description of the Drawings of the specification it is stated that BsAb HCN was used. Further, in Example 8 the it states that the sequences of the BsAbs are shown in SEQ ID NOs: 253-260. Note that SEQ ID NOs: 257 and 258 are the only SEQ ID NOs associated with the HCN structures listed in the specification:
SEQ 253 is anti-PD1 HC-Linker-2A3 (HCC heavy chain)
SEQ 254 is anti-PD1 LC1 (HCC light chain)
SEQ 255 is anti-PD1 HC1 (LCC light chain)
SEQ 256 is anti-PD1 LC-Linker-2A3 (LCC light chain)
SEQ 257 is 2A3-Linker-anti-PD1 HC (HCN heavy chain)
SEQ 258 is anti-PD1 LC2 (HCN light chain)
SEQ 259 is anti-PD1 HC2 (LCN heavy chain)
SEQ 260 is 2A3-Linker-anti-PD1 LC (LCN light chain)
Undue amount of experimentation: The MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). However, the unpredictable nature of the presently claimed invention is an important factor to be considered to determine if the presently claimed antibodies can be used in the presently claimed methods of treating and preventing any type of neoplasms in a subject. Given the single antibody embodiment used in the in vivo murine colon cancer model, the unpredictable nature as evidenced in the state of the art and in the instant specification, it is considered that performing the invention by one skilled in the art would be that of undue experimentation. Without further guidance, one of ordinary skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to make and use the invention commensurate in scope with these claims.
Response to argument
The applicants’ response filed on August 15, 2025 has been fully considered but is unpersuasive. The applicants argue the following:
Applicant herewith amends claim 1 to reflect that: i) the first antigen-binding moiety is clone 2A3 comprising SEQ ID NOs: 94-96, or its variants, ii) the second antigen-binding moiety is clone H1G4 comprising SEQ ID NOs: 221-226, and iii) the format of the bispecific antibody is HCN. Specifically, moiety (a) of amended claim 1 corresponds to clone 2A3 and moieties (b)-(e) of amended claim 1 correspond to variants of clone 2A3. The SEQ ID NOs recited in amended claim 1 are identified as pertaining to either clone 2A3 (SEQ ID NOs: 94-96), to variants of clone 2A3 (with SEQ ID NOs: 178-180 corresponding to variant 2A3 ML, SEQ ID NOs: 182-184 corresponding to variant 2A3 MI, SEQ ID NOs: 186-188 corresponding to variant 2A3 ML DT, also referred to as 2A3 LT (see Specification at page 144, line 2), and SEQ ID NOs: 190-192 corresponding to variant 2A3 ML DE), or to clone H1G4 (SEQ ID NOs: 221-226) in the Sequence Table found in Applicant’s as-filed Specification (see pages 132, 1385, and 137). Furthermore, the HCN format is described in amended claim 1 by the following recitation:
“wherein the first antigen-binding moiety comprises two anti-TIGIT antibodies, and the second antigen binding moiety comprises an anti-PD1 antibody comprising two antibody heavy chains and two antibody light chains, and
wherein the N-terminus of each of the two anti-PD1 heavy chains is linked to an anti-TIGIT antibody of the first antigen binding moiety.”
Support for these amendments can be found in, for example, the Sequence Table identified above, Example 8, and Figure 15 of Applicant’s as-filed specification.
Accordingly, no new matter is added. Applicant respectfully submits that claim 1 as amended is enabled at least because the Office has acknowledged enablement of “the specific antibody BsAb anti-TIGIT 2A3-Fc PD1-HCN version” (see Office Action at 5 and 10), which Applicant understands refers to the HCN version of the disclosed anti-TIGIT x anti-PD1 bispecific antibody of Example 8,' and because a person of ordinary skill in the art would reasonably extrapolate the anti-tumor effects of the above described bispecific antibody to certain variants wherein clone 2A3 of the first antigen-binding moiety is substituted by any of the 2A3 variants.
The present application discloses that in the process of generating new anti-TIGIT antibodies, clone 2A3 was identified for its highest antigen-binding affinity and potency. See Specification at Example 4 (page 143, first and second paragraphs), and Figure 5. Additionally, Example 4 on pages 143-144, bridging paragraph, describes the identification of two “hotspots” in CDR regions of 2A3, a methionine in CDR2 and an aspartic acid in CDR3 followed by serine, and it explains that mutations of methionine to leucine and isoleucine and mutations of aspartic acid to threonine and glutamic acid were carried out to produce variants 2A3 ML, 2A3 MI, 2A3 LT, and 2A3 ML_DE. The sequences of clone 2A3 and its variants are disclosed in the Sequence Table on pages 132 and 135 of Applicant’s as-filed specification. Applicant respectfully submits that, based on the similarity of the replacement residues and the limited number of modifications (one or two residues), a person having ordinary skill in the art would reasonably expect that those hotspot modifications may affect the 2A3 variants’ developability (e.g., ease of purification and shelf life) but would not affect their antigen-binding ability. For example, Example 4 on pages 1438-144, bridging paragraph, and Figure 9 disclose that the hotspot modified clone 2A3-LT-Fe exhibited similar binding affinity and potency compared to the parental clone 2A3-Fc. Because of the structural and functional similarity among clone 2A3 and its variants, a person having ordinary skill in the art would reasonably extrapolate the therapeutic effects of the 2A3-H1G4 HCN bispecific antibody to certain variants where clone 2A3 of the first antigen-binding moiety is substituted by the 2A3 variants of amended claim 1.
In addition, the applicants make a note on page 19 of “Remarks” that “The affinity matured anti-TIGIT clone used in the bispecific antibody of Example 8 is 2A3, and the affinity matured anti-PD1 clone “disclosed in PCT/US2017/050851” and used in the bispecific antibody of Example 8 (see Specification at page 147, lines 5-7) is H1G4.
However, the applicants argument is unpersuasive because arguments of counsel cannot take the place of evidence on the record. The applicants’ argument that “a person of ordinary skill in the art would reasonably extrapolate the anti-tumor effects of the above described bispecific antibody to certain variants wherein clone 2A3 of the first antigen-binding moiety is substituted by any of the 2A3 variants” appears to be a conclusory statement. The present claims are broader than the specific antibody BsAb anti-TIGIT 2A3-Fc PD1-HCN version comprising instant SEQ ID NOs: 257 and 258. Only this species of antibody appears to be enabled regarding the present claims for reasons provided in the of the rejection above.
Conclusion
No claims allowed.
The following related references may be applied in a future office action if appropriate:
WO-2018052818-A1 & attached Score result for PD-1. This reference discloses PD-1 antibodies and specific CDR sequences of the present claims but does not teach or suggest conjugates of such with the specific TIGIT CDR sequences of the present claims).
Kobayashi et al (Int J Hematol 2021 Vol 113, No 4, Abstract).
Liu (Biomarker Research 2019, Vol 7, No 25, pages 1-7).
Ma et al “A novel bispecific nanobody with PD-L1/TIGIT dual immune checkpoint blockade” (Biochemical & Biophysical Research Comm Vol 531, pages 144-151, published online August 8, 2020).
Xiao et al (Cancer Treatment and Research Comm Vol 29, published online 09/27/2021).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658