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 .
Claim Status
Claims 9, 15-29, and 35-46 are pending and under examination in the instant office action.
Priority
Applicant’s claim of foreign priority to Chinese application CN202210132762.1 is acknowledged and receipt of the certified copy of CN202210132762.1 is acknowledged. However, the certified copies are not English translations of the foreign priority application of record; accordingly, the instant claims are examined with a priority date to the filing of the PCT domestic benefit application of 14 February 2023.
Claim Interpretation
Regarding instant claims 15 and 16, the claim recite “wherein the second protein functional region of the anti-PD-1/anti-VEGFA bispecific antibody is an immunoglobulin” and wherein “the first protein functional protein region of the anti-PD-1/anti-VEGFA bispecific antibody is an immunoglobulin”. Regarding the definition of immunoglobulin, the specification states “In some embodiments of the present invention, in the bispecific antibody, the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. Since an immunoglobulin has two heavy chains, two single chain antibody molecules are linked to one immunoglobulin molecule”. A person of ordinary skill in the art, therefore, would understand from this statement that the instant “immunoglobulin” means a full-length antibody comprising two heavy and two light chains, each with a variable domain and a constant domain.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 9, 15-29, and 35-46 are rejected under 35 U.S.C. 103 as being obvious over WO2022089392 A1 to Li et. al. published 5 May 2022 and effectively filed 26 October 2020 (citations are to U.S. 20240002504 as English language equivalent); WO2021104302 to Zhang et. al. published 15 August 2019 (PTO-892 4/3/2026) (citations are to U.S. 20230027029 as English language equivalent); and Fan, Jia, et al. "AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein 1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus (vs) TIS plus BAT1706 as first-line treatment for advanced hepatocellular carcinoma (HCC)." (2022): TPS488-TPS488 published 19 January 2022.
The applied reference WO2022089392 A1 has a common assignee and inventors with the instant application. The Examiner notes that, even if the foreign priority date is perfected, based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Li et. al. teaches an anti-TIGIT antibody and pharmaceutical compositions thereof for tumor treatment (Abstract). Li et. al. teaches humanized variants (reads on comprising a non-CDR region from a human antibody, instant claim 19, and humanized antibody, instant claim 21) of the antibody 26B12H1L1, 26B12H4L1, 26B12H2L2, 26B12H3L2, 26B12H2L3, 26B12H3L3, 26B12H1L4, and 26B12H4L4 which have strong anti-TIGIT binding affinity and can reduce TIGIT activity [0008-0009]. The antibodies comprise heavy chains selected from SEQ ID NOs: 1, 11, 13, 15, and 17 and a light chain selected from SEQ ID NOs: 6, 19, 21, 23, and 25, which are 100% identical to instant SEQ ID NOs: 1, 11, 13, 15, and 17 and SEQ ID NOs: 6, 19, 21, 23, and 25 and specifically the pairings of SEQ ID NOs: 1 and 6, 11 and 19, 17 and 19, 13 and 21, 13 and 23, 15 and 21, 15 and 23, 11 and 25, or 17 and 25, which comprise CDRs 100% identical to instant SEQ ID NOs: 3-5 and SEQ ID NOs: 8, SAS, and 10 [0012-0022] (Reads on instant claims 9, 17, 18, 40). The anti-TIGIT antibody comprises an Ig gamma-1 chain C region (reads on IgG1) and a light chain constant region is Ig kappa chain C region ([0024], reads on instant claim 20), Li et. al. teaches a method comprising administering the anti-TIGIT antibody 26B12H2L2 on a CT26 colon cancer mouse xenograft tumor (Example 10, Fig. 18), wherein the anti-TIGIT antibody suppressed tumor growth compared to isotype control (Reads on instant claims 37 and 44; reads on colorectal cancer). Regarding claim 35, Li et. al. teaches a does administered to the mouse at 4mg/kg. Regarding claim 46, Li et. al. teaches that TIGIT and CD155 expression levels in cancer tissues of hepatocellular carcinoma patients are up-regulated [0004] and that in some embodiment the method of treating is a method of treating hepatocellular carcinoma [0061].
Li et. al. does not teach the combination comprising both the anti-TIGIT antibody and the anti-PD-1/VEGFA bispecific antibody comprising the CDRs as recited in claim 9.
This deficiency is resolved by Zhang et. al. and Fan et. al.
Zhang et. al. teaches an anti-VEGFA-anti-PD-1 bispecific antibody that comprises a PD-1 target first protein functional region and a VEGFA-targeted second protein functional region (Abstract). Zhang et. al. teaches the bispecific wherein the first protein functional region is an immunoglobulin and the second protein functional region is a single chain antibody; or the first protein functional region is a single chain antibody and the second protein functional region is an immunoglobulin [0041] (Reads on claims 15, 16, 21). Zhang et. al. teaches an embodiment wherein the amino acid sequence of the heavy chain of the immunoglobulin, which is 100% identical to residues 1-453 of instant SEQ ID NO: 27, and further comprises instant VH SEQ ID NO: 31 and CDRs SEQ ID NOs: 35-37:
Database : US-17-779-425A-24.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 2443 63.3 453 1 US-17-779-425A-24 ANTI-PD-1-ANTI-VEG
ALIGNMENTS
RESULT 1
US-17-779-425A-24
Query Match 63.3%; Score 2443; DB 1; Length 453;
Best Local Similarity 100.0%;
Matches 453; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
Qy 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA 240
Qy 241 AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 300
Qy 301 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS 360
Qy 361 RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 420
Qy 421 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 453
|||||||||||||||||||||||||||||||||
Db 421 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 453
And wherein the immunoglobulin further comprises the light chain of SEQ ID NO: 26, which is 100% identical to instant SEQ ID NO: 29 and comprises a VL of SEQ ID NO: 33 and instant CDRs SEQ ID NOs: 38, FTS, and 40 (Reads on claims 9, 28, 29, 38, 40, 43). Zhang et. al. teaches that the amino acid sequence of the VH of the single chain antibody is SEQ ID NO: 9 and the light chain variable region of the single chain antibody is SEQ ID NO: 17, and that it is linked to the C-terminus of the heavy chain of the immunoglobulin by a first linker fragment, and the VH of the single chain antibody is linked to the VL of the single chain antibody by a second linker fragment, wherein the linker fragments are SEQ ID NO: 18 or SEQ ID NO: 19 (a (GGGGS)3 linker and (GGGGS)4 linker) (identical to instant SEQ ID NOs: 52 and 53, reads on claims 22, 23, 41, 42) [0112]; these are 100% identical to the linkers and VH/VL fragments of the linkers and single chains of instant SEQ ID NO: 27 (and further comprise instant VH/VL SEQ ID NO: 41 and 43 and instant CDRs SEQ ID NOs: 45-47 and 48, RAN, and 50) residues 454-719 as shown below:
US-17-779-425A-9
Query Match 16.3%; Score 631; DB 1; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 474 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYY 533
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYY 60
Qy 534 PDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS 591
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS 118
US-17-779-425A-17
Query Match 14.6%; Score 562; DB 1; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 612 DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPS 671
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPS 60
Qy 672 RFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR 719
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR 108
(reads on instant claims 9, 25, 26, 27, 38, 39, 40, and 43).
Regarding instant claim 24, Zhang et. al. teaches the bispecific antibody according to the EU numbering system has the one of the following mutations: L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L325A, and G237A [0034-0039].
Zhang et. al. teaches the bispecific antibody or the pharmaceutical composition can be used alone or in combination, or used in combination with additional pharmaceutically active agents.
Regarding claim 35, Zhang et. al. teaches a dose of between 1mg/kg and 10mg/kg at that those skilled in the art can adjust the dosages [0173].
Regarding claim 36, Zhang et. al. teaches a kit comprising the bispecific antibody [0136].
Regarding instant claims 37, 44, 45, and 46, Zhang et. al. teaches “Yet another aspect of the present invention relates to a method for treating and/or preventing a malignant tumor, which comprises a step of administering to a subject in need thereof an effective amount of the bispecific antibody according to any embodiment of the present invention or the conjugate according to the present invention; preferably, the malignant tumor is selected from colon cancer, rectal cancer, lung cancer, liver cancer, ovarian cancer, skin cancer, glioma, melanoma, lymphoma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer, cervical cancer, esophageal cancer, microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancer, urothelial cancer, mesothelioma, endometrial cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and leukemia; preferably, the lung cancer is non-small cell lung cancer or small cell lung cancer; preferably, the non-small cell lung cancer is EGFR and/or ALK sensitive mutant non-small cell lung cancer; preferably, the liver cancer is hepatocellular carcinoma; preferably, the renal tumor is renal cell carcinoma; preferably, the breast cancer is triple negative breast cancer; preferably, the urothelial cancer is bladder cancer” [0167-0172].
Zhang et. al. teaches that the bispecific promotes the secretion of IFNγ and IL-2 in response to target cells expressing human PD-L1 and that the promotes activity better than nivolumab (Example 10, [0412-0413]). Zhang et. al. teaches that the invention includes a method for treating a malignant tumor comprising administering the bispecific antibody of the invention, including to microsatellite instability high and dMMR cancers; colon cancer; and hepatocellular cancer [0167].
Fan et. al. teaches that treatment with PD-1 inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. Fan et. al. teaches that co-inhibitory checkpoint receptor TIGIT is upregulated on T cells and NK cells in multiple solid tumors. Fan et. al. teaches a method of treating cancer with a combination of an anti-angiogenic agent similar to bevacizumab (an anti-VEGF antibody), an anti-PD-1 mAb that has demonstrated anti-cancer activity, and a novel humanized anti-TIGIT mAb that binds TIGIT with high specificity and affinity, blocking the interaction with TIGIT and its ligands on tumor cells “could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC” (See entire Abstract).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, create a combination of the humanized anti-TIGIT antibodies of Li et. al. and the anti-PD-1/anti-VEGFA antibodies of Zhang et. al. in order to benefit from the improved high-affinity anti-TIGIT antibodies as taught by Li et. al., the cytokine-inducing PD-1/anti-VEGFA bispecific that is more effective than nivolumab as taught by Zhang et. al. in a combination to treat cancer by inhibiting TIGIT and anti-angiogenic and PD-1 pathways simultaneously for improved treatment of cancer as taught by Fan et. al. This would have a reasonable expectation of success because Li et. al. and Zhang et. al. teach methods of treating cancer with the particular anti-TIGIT and anti-PD-1/VEGFA bispecific in individual combinations and given the teachings of Fan et. al. a person of ordinary skill in the art would expect additional anti-cancer effects from combining the two antibodies.
Regarding claim 35, this combination would result in combinations at the disclosed mass ration of 1:5-5:1 in order to benefit from effective dosing for each component antibody as taught by Zhang et. al., Li et. al., and Fan et. al. (e.g. a combination to make a pharmaceutical composition of 4 mg/mL of the anti-TIGIT antibody with the disclosed range of 1mg/mL to 10mg/mL of the anti-PD-1/VEGFA bispecific results in ratios of 4:1-2:5, which reads on a range of about 1:5-5:1). This would have a reasonable expectation of success because Zhang et. al. teaches that the dose may be optimized by a person of ordinary skill in the art.
Once the foreign priority date of the instant application is perfected by the filing of a translation as described in the priority section above, this rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
Copending Application No. 18250440
Claims 9, 15-29, and 35-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 and 28-32 of copending Application No. 18250440 in view of WO2021104302 to Zhang et. al. published 15 August 2019 (citations are to U.S. 20230027029 as English language equivalent); and Fan, Jia, et al. "AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein 1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus (vs) TIS plus BAT1706 as first-line treatment for advanced hepatocellular carcinoma (HCC)." (2022): TPS488-TPS488.
This is a provisional nonstatutory double patenting rejection.
Claim 1 of the ‘440 application teaches an anti-TIGIT antibody or antigen-binding fragment thereof wherein the anti-TIGIT antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region of the antibody comprises HCDR1-HCDR3 with amino acid sequences set forth in SEQ ID NOs: 3-5, respectively, and the light chain variable region of the antibody comprises LCDR1-LCDR3 with amino acid sequences set forth in SEQ ID NOs: 8- 10, respectively (identical to instant SEQ ID NOs: 3-5 and SEQ ID NOs: 8, SAS, and 10. Claim 2 teaches wherein the heavy chain variable region of the antibody comprises an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, and SEQ ID NO: 17; and the light chain variable region of the antibody comprises an amino acid sequence selected from SEQ ID NO: 6, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, and SEQ ID NO: 25 (instant claim 17). Claim 3 teaches particular pairs of heavy and light chain variable regions from the sequences of claim 2, for example wherein the heavy chain variable region of the antibody comprises an amino acid sequence set forth in SEQ ID NO: 1, and the light chain variable region of the antibody comprises an amino acid sequence set forth in SEQ ID NO: 6 (instant claim 18). Claim 4 teaches The anti-TIGIT antibody or the antigen-binding fragment thereof according to claim 1, wherein the anti-TIGIT antibody or the antigen-binding fragment thereof is selected from Fab, Fab', F(ab')2, Fv, a single chain antibody, a humanized antibody, a chimeric antibody, and a diabody (instant claim 21). Claim 5 teaches the anti-TIGIT antibody or the antigen-binding fragment thereof according to claim 1, wherein the antibody comprises a non-CDR region is derived from a human antibody (instant claim 19). Claim 6 teaches the anti-TIGIT antibody or the antigen-binding fragment thereof according to claim 1, wherein the anti-TIGIT antibody comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region of the antibody is Ig gamma-1 chain C region or Ig gamma-4 chain C region; and the light chain constant region of the antibody is Ig kappa chain C region (instant claim 20). Claims 21 and 22 teach a pharmaceutical composition, comprising the anti-TIGIT antibody or the antigen-binding fragment thereof according to claim 1and a pharmaceutically acceptable carrier and/or excipient and further comprising one or more anti-PD-1 antibodies. Claim 23 teaches the composition wherein a mass ratio of the anti-TIGIT antibody or the antigen-binding fragment thereof to the anti-PD-1 antibody or the anti-PD-L1 antibody is (1:5) - (5:1), based on the mass of the antibodies (instant claim 35). Claim 24 teaches a combination product, comprising a first product and a second product in separate packages, wherein the first product comprises the anti-TIGIT antibody or the antigen-binding fragment thereof according to claim 1; the second product comprises at least one anti-PD-1 antibody or at least one anti-PD-L1 antibody; wherein the first product and the second product further independently comprise one or more pharmaceutically acceptable adjuvants (reads on claims 9, 36, 40). Claim 25 teaches the combination product according to claim 24, wherein a mass ratio of the anti- TIGIT antibody or the antigen-binding fragment thereof to the anti-PD-1 antibody or the anti- PD-L1 antibody is (1:5) - (5:1), based on the mass of the antibodies (instant claim 35). Claims 28 and 29 teaches a method of treating a tumor comprising administering the antibody of claim 1 wherein the tumor is selected from liver cancer, kidney cancer, brain tumor, urothelial carcinoma, bone tumor, cholangiocarcinoma, non-small cell lung cancer, small cell lung cancer (reads on claims 37, 44, and 45), breast cancer, ovarian cancer, colorectal cancer, melanoma, pancreatic cancer, cervical tumor, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (reads on claims 37, 44, and 45), B- lymphoma, ovarian cancer, plasma cell cancer; and endometrial cancer, prostate cancer, and testicular cancer.
‘440 does not teach the combination comprising both the anti-TIGIT antibody and the anti-PD-1 antibody or antigen binding fragment thereof, wherein the anti-PD-1 antibody is the anti-PD-1/VEGFA bispecific antibody comprising the CDRs as recited in claim 9.
This deficiency is resolved by Zhang et. al. and Fan et. al.
Zhang et. al. teaches an anti-VEGFA-anti-PD-1 bispecific antibody that comprises a PD-1 target first protein functional region and a VEGFA-targeted second protein functional region (Abstract). Zhang et. al. teaches the bispecific wherein the first protein functional region is an immunoglobulin and the second protein functional region is a single chain antibody; or the first protein functional region is a single chain antibody and the second protein functional region is an immunoglobulin [0041] (Reads on claims 15, 16, 21). Zhang et. al. teaches an embodiment wherein the amino acid sequence of the heavy chain of the immunoglobulin, which is 100% identical to residues 1-453 of instant SEQ ID NO: 27, and further comprises instant VH SEQ ID NO: 31 and CDRs SEQ ID NOs: 35-37:
Database : US-17-779-425A-24.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 2443 63.3 453 1 US-17-779-425A-24 ANTI-PD-1-ANTI-VEG
ALIGNMENTS
RESULT 1
US-17-779-425A-24
Query Match 63.3%; Score 2443; DB 1; Length 453;
Best Local Similarity 100.0%;
Matches 453; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
Qy 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA 240
Qy 241 AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 300
Qy 301 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS 360
Qy 361 RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK 420
Qy 421 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 453
|||||||||||||||||||||||||||||||||
Db 421 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 453
And wherein the immunoglobulin further comprises the light chain of SEQ ID NO: 26, which is 100% identical to instant SEQ ID NO: 29 and comprises a VL of SEQ ID NO: 33 and instant CDRs SEQ ID NOs: 38, FTS, and 40 (Reads on claims 9, 28, 29, 38, 40, 43). Zhang et. al. teaches that the amino acid sequence of the VH of the single chain antibody is SEQ ID NO: 9 and the light chain variable region of the single chain antibody is SEQ ID NO: 17, and that it is linked to the C-terminus of the heavy chain of the immunoglobulin by a first linker fragment, and the VH of the single chain antibody is linked to the VL of the single chain antibody by a second linker fragment, wherein the linker fragments are SEQ ID NO: 18 or SEQ ID NO: 19 (a (GGGGS)3 linker and (GGGGS)4 linker) (identical to instant SEQ ID NOs: 52 and 53, reads on claims 22, 23, 41, 42) [0112]; these are 100% identical to the linkers and VH/VL fragments of the linkers and single chains of instant SEQ ID NO: 27 (and further comprise instant VH/VL SEQ ID NO: 41 and 43 and instant CDRs SEQ ID NOs: 45-47 and 48, RAN, and 50) residues 454-719 as shown below:
US-17-779-425A-9
Query Match 16.3%; Score 631; DB 1; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 474 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYY 533
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYY 60
Qy 534 PDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS 591
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS 118
US-17-779-425A-17
Query Match 14.6%; Score 562; DB 1; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 612 DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPS 671
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPS 60
Qy 672 RFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR 719
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR 108
(reads on instant claims 9, 25, 26, 27, 38, 39, 40, and 43).
Regarding instant claim 24, Zhang et. al. teaches the bispecific antibody according to the EU numbering system has the one of the following mutations: L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L325A, and G237A [0034-0039].
Zhang et. al. teaches the bispecific antibody or the pharmaceutical composition can be used alone or in combination, or used in combination with additional pharmaceutically active agents.
Regarding claim 35, Zhang et. al. teaches a dose of between 1mg/kg and 10mg/kg at that those skilled in the art can adjust the dosages [0173].
Regarding claim 36, Zhang et. al. teaches a kit comprising the bispecific antibody [0136].
Regarding instant claims 37, 44, 45, and 46, Zhang et. al. teaches “Yet another aspect of the present invention relates to a method for treating and/or preventing a malignant tumor, which comprises a step of administering to a subject in need thereof an effective amount of the bispecific antibody according to any embodiment of the present invention or the conjugate according to the present invention; preferably, the malignant tumor is selected from colon cancer, rectal cancer, lung cancer, liver cancer, ovarian cancer, skin cancer, glioma, melanoma, lymphoma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer, cervical cancer, esophageal cancer, microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancer, urothelial cancer, mesothelioma, endometrial cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and leukemia; preferably, the lung cancer is non-small cell lung cancer or small cell lung cancer; preferably, the non-small cell lung cancer is EGFR and/or ALK sensitive mutant non-small cell lung cancer; preferably, the liver cancer is hepatocellular carcinoma; preferably, the renal tumor is renal cell carcinoma; preferably, the breast cancer is triple negative breast cancer; preferably, the urothelial cancer is bladder cancer” [0167-0172].
Zhang et. al. teaches that the bispecific promotes the secretion of IFNγ and IL-2 in response to target cells expressing human PD-L1 and that the promotes activity better than nivolumab (Example 10, [0412-0413]). Zhang et. al. teaches that the invention includes a method for treating a malignant tumor comprising administering the bispecific antibody of the invention, including to microsatellite instability high and dMMR cancers; colon cancer; and hepatocellular cancer [0167].
Fan et. al. teaches that treatment with PD-1 inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated hepatocellular carcinoma (HCC). Fan et. al. teaches that co-inhibitory checkpoint receptor TIGIT is upregulated on T cells and NK cells in multiple solid tumors. Fan et. al. teaches a method of treating HCC (reads on claim 46) with a combination of an anti-angiogenic agent similar to bevacizumab (an anti-VEGF antibody), an anti-PD-1 mAb that has demonstrated anti-cancer activity, and a novel humanized anti-TIGIT mAb that binds TIGIT with high specificity and affinity, blocking the interaction with TIGIT and its ligands on tumor cells “could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC” (See entire Abstract).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, create a combination of the humanized anti-TIGIT antibodies of ‘440 and the anti-PD-1/anti-VEGFA antibodies of Zhang et. al. in order to benefit from a particular embodiment of the anti-TIGIT and anti-PD-1 combination as taught by ‘440 comprising the improved high-affinity anti-TIGIT antibodies as taught by ‘440., the cytokine-inducing PD-1/anti-VEGFA bispecific that is more effective than nivolumab as taught by Zhang et. al. in a combination to treat cancer by inhibiting TIGIT and anti-angiogenic and PD-1 pathways simultaneously for improved treatment of cancer as taught by Fan et. al. This would have a reasonable expectation of success because ‘440 and Zhang et. al. teach methods of treating cancer with the particular anti-TIGIT and anti-PD-1/VEGFA bispecific in individual combinations and given the teachings of Fan et. al. a person of ordinary skill in the art would expect additional anti-cancer effects from combining the two antibodies.
Regarding claim 46, It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to treat hepatocellular carcinoma in particular as taught by Fan et. al. with the composition as a species of treating liver cancer as taught by ‘440 in order to benefit from the treatment combination of anti-TIGIT, anti-VEGF, and anti-PD-1 as taught by Fan et. al. with the particular effective anti-TIGIT in combination with anti-PD-1 as taught by Fan et. al. This would have a reasonable expectation of success because ‘440, Zhang et. al., and Fan et. al. all treat forms of liver cancer with antibodies shown to have anti-TIGIT, anti-PD-1, and anti-VEGFa antibodies effective for the treatment of cancer.
Copending Application No. 18291128
Claims 9, 15-29, and 35-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18291128 in view of WO2021104302 to Zhang et. al. published 15 August 2019 (citations are to U.S. 20230027029 as English language equivalent); and Fan, Jia, et al. "AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein 1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus (vs) TIS plus BAT1706 as first-line treatment for advanced hepatocellular carcinoma (HCC)." (2022): TPS488-TPS488.
The ’128 application teaches a pharmaceutical composition or a kit comprising an anti-TIGIT antibody or antigen-binding fragment thereof and an anti-CTLA4-anti-PD1 bispecific antibody or antigen-binding fragment thereof, wherein the anti-TIGIT antibody comprises VH SEQ ID NO: 1 HCDR1-HCDR3 of SEQ ID NOs:3-5 (identical to instant SEQ ID NO: 1 and CDRs SEQ ID NOs: 3-5) and VL of SEQ ID NO: 6 comprising LCDR1-LCDR3 of SEQ ID NOs: 8-10 (identical to instant CDRs SEQ ID NOs: 8, SAS, and 10) (claim 1, reads on instant claims 9, 17-18); wherein the bispecific antibody comprises a first protein functional region targeting PD-1, wherein the first protein function region is an immunoglobulin or a single chain antibody (claim 1; instant claim 21). Claim 2 teaches wherein the anti-TIGIT VH is from SEQ ID NOs: 1, 11, 13, 15, and 17 (identical to instant SEQ ID NOs: 1, 11, 13, 15, and 17) and the VL is from SEQ ID NOs: 6, 19, 21, 23, and 25 (identical to instant SEQ ID NOs: 6, 19, 21, 23, and 25) and the particular pairs of heavy and light chain variable regions, for example wherein the heavy chain variable region of the antibody comprises an amino acid sequence set forth in SEQ ID NO: 1, and the light chain variable region of the antibody comprises an amino acid sequence set forth in SEQ ID NO: 6 (instant claims 17 and 18); wherein the anti-TIGIT antibody comprises a heavy chain constant region Ig gamma-1 chain C region and a light chain Ig kappa chain C region (instant claim 20); wherein the anti-TIGIT antibody or the antigen-binding fragment thereof is selected from Fab, Fab', F(ab')2, Fd, Fv, dAb, a complementarity determining region fragment, a single chain antibody, a humanized antibody, a chimeric antibody, or a diabody (instant claim 21). Claim 4 teaches the pharmaceutical composition according to claim 1 wherein the ratio of the anti-TIGIT antibody and the bispecific are present in a mass ratio on an antibody basis of 1:5-5:1 (instant claim 35). Claim 5 teaches a kit comprising the anti-TIGIT antibody and the anti-CTLA4-anti-PD-1 bispecific antibody wherein the combination are present at a mass ratio of 1:5-5:1 (instant claims 35 and 36). Claim 6 teaches a method for treating a tumor comprising administering the anti-TIGIT and the anti-CTLA4/PD-1 bispecific, wherein the tumor is selected from breast cancer, ovarian cancer, colorectal cancer, cervical tumor, multiple myeloma, non- Hodgkin's lymphoma, B-lymphoma, plasma cell cancer, head and neck cancer, brain cancer, throat cancer, nasopharyngeal cancer, oesophageal cancer, esophageal squamous cancer, thyroid cancer, mesothelioma, adenocarcinoma (e.g., pancreatic cancer), lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), breast cancer, liver cancer (e.g., hepatocellular carcinoma and hepatobiliary cancer), gastric cancer, gastrointestinal cancer, intestinal cancer (e.g., colon cancer and colorectal cancer), biliary tract cancer (e.g., cholangiocarcinoma), kidney cancer, fallopian tube cancer, endometrial cancer, cervical cancer, bladder cancer, urothelial carcinoma, prostate cancer, testicular cancer, skin cancer, melanoma, myeloma (e.g., multiple myeloma), non-Hodgkin's lymphoma, B-lymphoma, plasma cell carcinoma, leukemia, lymphoma, bone cancer, osteosarcoma, chondrosarcoma, high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) solid tumors (instant claims 37, 44, 45, 46).
‘128 does not teach the combination and method comprising the particular anti-PD-1/anti-VEGFA bispecific comprising the CDRs as recited in claim 9.
This deficiency is resolved by Zhang et. al. and Fan et. al.
The teachings of Zhang et. al. and Fan et. al. are in the 103 and NSDP rejections above and are incorporated by reference herein.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, create a combination of the humanized anti-TIGIT antibodies of ‘128 and the anti-PD-1/anti-VEGFA antibodies of Zhang et. al. in order to benefit from a particular embodiment of the anti-TIGIT and anti-PD-1 bispecific combination as taught by ‘128, comprising the improved high-affinity anti-TIGIT antibodies as taught by ‘128, by substituting the cytokine-inducing PD-1/anti-VEGFA bispecific that is more effective than nivolumab as taught by Zhang et. al. for the anti-PD-1/anti-CTLA4 bispecific of ‘128, resulting in a combination to treat cancer by inhibiting TIGIT and anti-angiogenic and PD-1 pathways simultaneously for improved treatment of cancer as taught by Fan et. al. This would have a reasonable expectation of success because ‘128 and Zhang et. al. teach methods of treating cancer with the particular anti-TIGIT and anti-PD-1/VEGFA bispecific in individual combinations and given the teachings of Fan et. al. a person of ordinary skill in the art would expect additional anti-cancer effects from combining the two antibodies.
Copending Application No. 19519159
Claims 9, 15-29, and 35-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 7-8, 10-12, 13, 17-18, 21-23, 32-33, 35-38 of copending Application No. 19519195.
‘159 teaches a pharmaceutical combination comprising a first bispecific and a second bispecific, wherein the first bispecific comprising a first functional protein region binding to PD-1 and a second protein functional region binding to VEGFA, wherein the first protein function region comprises a VH1 and VL1 comprising HCDRs SEQ ID NOs: 1-3 and LCDRs SEQ ID NOs: 4-6 (claim 1), wherein the VH1 and VL1 are selected from SEQ ID NOs: 20 and 24 and SEQ ID NOs: 22, 26, and 35, respectively (claim 2; SEQ ID NO: 24 is identical to instant SEQ ID NO: 41 and SEQ ID NO: 35 is identical to instant SEQ ID NO: 43; instant claims 9, 26-27, 38-39); and wherein the second protein functional region comprises a VH2 and VL2 comprising HCDRs SEQ ID NOs: 7-9 and LCDRs SEQ ID NOs: 10-12 (claim 1) and the VH2 and VL2 are SEQ ID NOs: 31 and SEQ ID NO: 33 (claim 4; SEQ ID NOs: 31 and 33 are identical to instant SEQ ID NOs: 31 and 33; instant claims 9, 28-29, 38-39); and wherein the second bispecific comprises a third protein functional region specifically binding to TIGIT and comprising HCDRs 13-15 and LCDRs 16-18 (claim 1) and the VH3 and VL3 are selected from SEQ ID NOs: 46, 50, 52, 54, 56 and SEQ ID NOs: 48, 58, 60, 62, and 64 (claim 5) and particular pairs (e.g. SEQ ID NO: 46 and SEQ ID NO: 48) identical to the VH and VL of the instant anti-TIGIT antibodies of as recited in instant claims 17 and 18 (e.g. instant SEQ ID NO: 46 is identical to instant SEQ ID NO: 1 and SEQ ID NO: 48 is identical to instant SEQ ID NO: 6; instant claims 9, 17-18, 37, 40). Regarding claim 19, SEQ ID NOs: 46, 50, 52, 54, 56 and SEQ ID NOs: 48, 58, 60, 62, and 64 are humanized antibodies with human non-CDR (framework) regions. Claim 8 teaches the pharmaceutical combination wherein the first protein functional region is an IgG (reads on an immunoglobulin) and the second protein functional region is a single-chain variable fragment or the first protein functional region is a single-chain variable fragment and the second protein functional region is an IgG (reads on an immunoglobulin; instant claims 15 and 16; single-chain antibody reads on instant claim 21). Claim 10 teaches the combination of claim 8 wherein the IgG is IgG1 (instant claim 20). Claim 11 teaches wherein the IgG1 heavy chain comprises the mutations selected from a group including L234A and L325A (instant claim 24). Claim 13 teaches wherein the second protein functional region is an IgG wherein the heavy chain comprises one of SEQ ID NOs: 38, 40, 42 (SEQ ID NO: 42 is 100% identical to residues 1-453 of instant SEQ ID NO: 27), and the light chain comprises SEQ ID NO: 33 (100% identical to instant SEQ ID NO: 33), and the third protein is an IgG wherein the heavy chain comprises an SEQ ID NO: 66 or 70 (SEQ ID NO: 66 comprises a VH identical to instant SEQ ID NO: 13 and an IgG constant region; reads on instant claims 9 and 40) and the light chain comprises SEQ ID NO: 68 (comprising VL identical to instant SEQ ID NO: 21 and a kappa light chain constant region; instant claim 20); and that the first protein functional region and the second protein functional region are linked directly or via linker. Claim 17 teaches the linker is SEQ ID NO: 91 or 92 or comprises SEQ ID NO: 36, 37, or 83 (SEQ ID NO: 36 and 37 are identical to instant linkers 52 and 53; instant claims 22-23, 41-42). Claim 18 teaches particular structures of the bispecific such as wherein the second protein functional region is one IgG, and the first protein functional region is two single-chain variable fragments, and the single-chain variable fragments are linked to the C-termini or N-termini of the two heavy chains of the second protein functional region, respectively (reads on claim 25, 40, 43). Claim 23 teaches wherein the mass ratio of the first bispecific to the second bispecific is selected among ranges including 5:1 to 1:5 and further comprises a package insert (reads on kit; instant claims 35-36). Claim 32 recites a method for treating or preventing a tumor, comprising a step of administering to a subject the composition of claim 1 (reads on claim 37). Claim 37 teaches wherein the tumor is selected from a group; claim 38 teaches wherein the lung cancer is non-small cell lung cancer or small cell lung cancer (instant claims 37, 44, and 45) and wherein the liver cancer is hepatocellular carcinoma (instant claim 46). Thus, although the claims are not identical, they are not patentably distinct because the ‘159 application makes obvious a species of the instant invention.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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