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 .
Priority
The application is a 371 application, filed 09/11/2023, of PCT application PCT/EP2022/056037, filed 03/09/2022, which claims priority benefits from Foreign Application No. EP21161460.7, filed 03/09/2021. The effective filing date of this application is 03/09/2021, the filing date of Foreign Application No. EP21161460.7.
Claims Status
Amendments filed 07/06/2026 are entered.
Claims 1, 3, 6, 7, 14-17, 22, 24, 27, 29-31, 38-40, 45 are amended.
Claim 46 is new.
Claims 2, 4, 5, 10-13, 20, 21, 23, 25, 26, 28, 32, 36, 41-44 are cancelled.
Claims 1, 3, 6, 7-9, 14-19, 22, 24, 27, 29-31, 33-35, 37-40, 45, and 46 are rejected.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/28/2026 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections/Rejections
Drawings Objections
The previous objections to the Drawings are withdrawn in response to the amendments to the drawings, filed 07/06/2026, fixing the label for Figure 4.
Claim Objections
The previous objections to the Claims are withdrawn in response to the amendments to the Claims, filed 07/06/2026. The amendments resolve the minor informalities by cancelling claim 26 and deleting the redundant limitation in claim 22.
Claim Rejections - 35 USC § 112(d)
The previous 35 USC § 112(d) rejections to the Claims are withdrawn in response to the amendments to the Claims, filed 07/06/2026. The amendments change the rejected claims into independent forms and therefore render the previous rejection regarding not further limiting its parent claim moot.
Claim Rejections - 35 USC § 112(b)
The previous 35 USC § 112(b) rejections to the Claims are withdrawn in response to the amendments to the Claims, filed 07/06/2026. The amendments resolve the indefiniteness of the claims by distinctly reciting defined doses in claims 22, 24, 26, 27, and 31; by distinctly claiming that the solid cancer options are all alternative options of each other, instead of the second list of solid cancers possibly further limiting the first list in claim 40; and by reciting which antibody is being discussed in claim 45.
35 USC § 112(a) - Written Description
The previous 35 USC § 112(a) Written Description rejections to the claims are withdrawn in response to the amendments to the Claims, filed 07/06/2026.
(A) The amendments resolve the lack of written description for the combination of sequences that define the claimed first antibody molecule by reciting the exact ordering and combination of CDR or VH/VL sequences.
(B) The amendments resolve the lack of written description for the minimum effective therapeutic dose and maximum tolerated therapeutic dose of the claimed second antibody molecule. The amendments specified the different doses to be the dose of the second antibody molecule when it administered alone (i.e. monotherapy), which has written description support in the art or in the disclosure. It eliminates the doses of the second antibody when it is administered with other therapies (i.e. combination therapies) which lacked written description in the art since it encompassed a broad genus of doses varying by the combined and/or synergistic effects with the other drug(s).
35 USC § 112(a) - Enablement
The previous 35 USC § 112(a) Enablement rejections to claims 29 and 30 are withdrawn in response to the amendments to the Claims, filed 07/06/2026.
The amendments that narrowed the scope of the doses to the dose of the second antibody administered alone also resolve the enablement rejections because one skilled of the art is now able to know what the required comparison dose is. The broadest reasonable interpretation of the previously presented claims encompassed doses of the second antibody in both monotherapy and in all possible combination therapies. The minimum therapeutic dose or recommended therapeutic doses likely differs between the second antibody alone versus in a combination therapy. The art and the disclosure does not teach the minimum therapeutic dose or recommended therapeutic doses of the second antibody in every combination therapy, let alone for every cancer, and it would have required a high level of experimentation just to determine this comparison dose first, before even being able to find doses lower than this that are effective in the particularly claimed combination. It was for those reasons that the enablement rejection was previously given.
Claim Rejections - 35 USC § 103
The previous 35 USC § 103 rejections to claims 10-13, 26, and 41-44 are withdrawn in response to the amendments to the Claims, filed 07/06/2026. Claims 10-13, 26, and 41-44 are cancelled, rendering the rejections moot.
Maintained Objections/Rejections
Nucleotide and/or Amino Acid Sequence Disclosures
The previous objection to the Specification regarding the Incorporation by Reference statement of the sequence listing is maintained and updated in response to the amendments to the Specification, filed 07/06/2026. The name of the file recited should be the name of the originally submitted file, which is “eolf-othd-000001.txt”. The file size should be recited in bytes, which is 92497 bytes.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES (ST.25)
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
The information in the Incorporation by Reference paragraph does not match the sequence listing and format requirements. The original sequence file name, which should appear in the Incorporation by Reference paragraph, is eolf-othd-000001.txt and the file size is 92497 bytes.
Claim Rejections - 35 USC § 103
The previous 35 USC § 103 rejections are maintained and/or updated to address the amended claims 14-15, 22, 24, 27, 29-31, 38, 45 and new claim 46. New rejections under 35 USC § 103 are presented for claims 29, 30, and 46 in response to the amendments.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6-9, 14-19, 40-44 are rejected under 35 U.S.C. 103 as being unpatentable over Frendeus et al (WO2019138005A2; published 07/18/2019; IDS filed 02/20/2024, Foreign Patent reference 3) in view of Wei et al (Wei, S., et al, Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies, PNAS, vol. 116, no. 45; published 11/05/2019).
Regarding claim 1, Frendeus et al teaches a combination comprising: an antibody molecule that specifically binds to FcyRIIb via its Fab region, and that lacks an Fc region or has reduced binding to Fcy receptors via its Fc region; and an antibody molecule that specifically binds to PD-1 or PD- L1, use in treating cancer in a patient (page 47, line 25 to page 48, line 11). Frendeus et al teaches a combination comprising: a first antibody molecule that specifically binds to FcyRllb via its Fab region, and that lacks an Fc region or has reduced binding to Fcy receptors via its Fc region; and an antibody molecule that specifically binds to CTLA-4 and that binds to at least one Fcy receptor via its Fc region (page 47, lines 4-23), for use in treating cancer in a patient. Together, these two combinations of two antibodies are relevant to claim 1.
Frendeus et al further teaches these combinations in a method for treating cancer in a patient, the method comprising administering to the patient the combination of antibodies, as is relevant to claim 3 (page 47-48 and Abstract).
Frendeus et al further teaches these combinations in a pharmaceutical composition, as is relevant to claim 6 (page 2, line 17-25; Abstract).
Frendeus et al further teaches these combinations in a kit, as is relevant to claim 7 (page 2, line 26-34; Abstract).
Frendeus et al does not explicitly teach all three antibodies together in one combination, as is relevant to claims 1, 3, 6, 7, and dependent claims.
Frendeus et al does not explicitly teach wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and/or an antibody molecule that specifically binds to CTLA-4, as is relevant to claims 1, 3, 6, 7, and dependent claims.
Frendeus et al does not explicitly teach wherein the cancer is a relapsed and/or refractory cancer, as is relevant for claim 18.
However, Wei et al teaches a combination of full-length (Methods, paragraph 1) anti-CTLA-4 and anti-PD-1 blockade therapy has enhanced efficacy over monotherapy by both additive effects and combination therapy-specific effects (Abstract). Wei et al further teaches that these effect and mechanism differences may make combination therapy more efficacious in the less immunogenic tumor types refractory to monotherapies (Discussion, paragraph 2).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to combine the prior art elements according to known methods to yield predictable results. In light of the teachings regarding all possible combinations of two antibodies using each of the three antibodies in the claims, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, to combine these combinations to arrive at the instant combination of all three antibodies, since each combination is shown to have enhanced efficacy over monotherapy. It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to apply the combination therapy of 3 antibodies to tumors refractory, and therefore, resistant, to monotherapies, considering the teachings of Wei et al regarding the enhanced effects of combination therapies compared to monotherapies of the same components.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the three antibodies already taught in dual-antibody combination therapies because they all, generally but differently, work to remove negative regulations of immune cells. WO’ 005 already provides the motivation to combine antibodies binding FcyRIIB without an Fc region or reduced Fcy receptors binding via its Fc region with antibodies binding receptors on immune cells with Fcy receptor binding via its Fc region, specifically, immune checkpoint inhibitor antibodies binding CTLA-4 and PD-L1 (page 47-48). Wei et al then teaches the motivation to combine antibodies binding CTLA-4 and PD-L1. Furthermore, one skilled in the art, before the effective filing date of the instant application, would be motivated to apply these combinations towards tumors that were resistant or refractory to monotherapy treatment by anti-CTLA-4 and/or anti-PD1/PDL1 since the addition of the antibodies binding FcyRIIB with no or reduced Fcy receptor binding via a Fc region can augment these checkpoint inhibitors, as taught by Frendeus et al. These combinations could enable treatment tumors that should theoretically benefit from checkpoint inhibitors but could benefit from a secondary antibody that removes obstacles to their benefits.
Claims 8, 9, 14-19 depend on claim 3. Claim 40 depends on claim 17, which depends on claim 16, which depends on claim 3. The teachings of the references regarding the parent claims are incorporated in their entirety for the dependent claims and discussed further below, as is relevant for each claim.
Frendeus et al further teaches wherein the first antibody molecule lacks the Fc region or has an aglycosylated Fc region (Abstract), arriving at all the limitations of claim 8.
Frendeus et al further teaches wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin (page 15, lines 16-24), and the constant regions and the constant regions with the N297Q used throughout their human antibody examples are of human origin (page 16, line 4) arriving at all the limitations of claim 9.
Frendeus et al further teaches wherein the cancer is a FcyRIIb-positive B-cell cancer or is a FcyRIIb-negative cancer (Abstract; page 2-3 section: summary of the invention), arriving at all the limitations of claim 16, and further, wherein the FcyRIIb-negative cancer is a solid cancer (page 36, lines 6-7), arriving at all the limitations of claim 17.
Frendeus et al further teaches combination methods specifically with CT26 and MC38 tumor models, which are both carcinomas (page 47), meeting the limitations of claim 40.
Frendeus et al further teaches wherein the anti-PD-1 or PD-L1 antibody and/or the anti-CTLA-4 antibody is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin (page 31, lines 1-9), arriving at all the limitations of claim 19.
Frendeus et al further teaches combinations of sequences for the first antibody molecules that arrive at the limitations of claims 14-15. For example, Frendeus et al teaches the antibody clone 1A01 (page 17) which comprises of SEQ ID NO: 3 and SEQ ID NO: 27 for its VH sequence and VL sequence, respectively, which has a 100% identity match to the instant SEQ ID NO: 3 and SEQ ID NO: 27 (see Sequence Search Results), which is one possible embodiment for the VH and VL pairings from the instant claims. This particular VH and VL pairing comprises of SEQ ID NO: 51-53, and 54-56 for its CDRH1-3 and CDRL1-3, respectively, which matches with the instant SEQ ID NO: 51-56 (see Sequence Search Results), which is one possible embodiment of CDR combinations from the instant claims. Frendeus et al teaches multiple other antibody clones that meet the instantly claimed sequence limitations for the first antibody molecule (page 17-30).
Claims 22, 24, 27, 29, 30, 33, 35, 37-39, and new claim 46 are rejected under 35 U.S.C. 103 as being unpatentable over Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and Long et al (Long, G., et al, Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial, The Lancet Oncology, 18: 1202-10; published 07/17/2017).
The teachings of the references regarding claim 22 are incorporated in its entirety for dependent claims and discussed further below, as is relevant for each claim.
Frendeus et al teaches a method for treating cancer in a patient, the method comprising administering to the patient: a first antibody molecule that specifically binds to FcyRllb via its Fab region, and that lacks an Fc region or has reduced binding to Fcy receptors via its Fc region; and a second antibody molecule that specifically binds to CTLA-4 and that binds to at least one Fcy receptor via its Fc region; for use in treating cancer in a patient (page 47, lines 4-23), as is relevant to claims 22 and 26. Inherent to that method of treating is a combination comprising the antibodies; Frendeus et al also teaches a combination comprising: the first antibody molecule that specifically binds to the FcγFIIB via its Fab region, and that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region; and the second antibody molecule that specifically binds to CTLA-4 and that binds to at least one Fcγ receptor via its Fc region, as is relevant to claim 24 (page 47, lines 4-23). Frendeus et al further teaches this combination in a kit, as is relevant to claim 27 (page 47, lines 4-23).
Frendeus et al does not explicitly teach wherein the dose of the second antibody molecule that is administered is lower than the recommended therapeutic dose of the second antibody molecule, i.e. the anti-CTLA4 antibody, when administered alone, as is necessary for claims 22, 24, and 27. Frendeus et al does not explicitly teach the dose of the second antibody is lower than the minimum therapeutic dose of the second antibody when administered alone, as is relevant to claim 29 or that the therapeutic effect of the first antibody and second antibody at the lower dose is comparable to the therapeutic effect of the second antibody molecule when administered alone at the recommended therapeutic dose of the second antibody, as is relevant to claim 30.
However, Frendeus et al does teach that lower doses of either antibody in the combination may be used and a physician could determine the most suitable dosage depending, in part, on the response of the particular patient and length of administration (page 33, lines 20-25).
Additionally, Bhattacharya et al also teaches formulations of ant-CTLA4 alone and in combination with anti-PD-1 antibodies to treat cancers (Abstract) and that these formulations may be administered with one or more additional biotherapeutic agents, suggesting anti-CTLA4 alone can be combined with other biotherapeutics (page 46, lines 12-14). Bhattacharya et al further teaches that dosage of the additional therapeutic agents in the combination should depend on achieving an acceptable level of side effects, as well as dose frequency, cancer severity, and individual patient’s response to the therapeutics (page 46, line 37 – page 47, line 17). Bhattacharya et al further teaches a preferred dose protocol is one involving the maximal dose or dose frequency that avoids significant undesirable side effects (page 47, line 31-32).
Furthermore, Long et al, specifically teaches a reduced-dose ipilimumab (a CTLA-4-binding antibody) in combination with a standard-dose of another checkpoint inhibitor antibody for treating patients with advanced melanoma (page 1202, section: Interpretation).
In summary, Frendeus et al teaches the combination of the first and second antibodies as instantly claimed. Frendeus et al teaches lower doses of one or both antibodies is envisioned. Bhattacharya et al provides further rationale for lower doses of drugs in a combination. Long et al, specifically teaches reduced dose of the CTLA-4-binding antibody from its monotherapy dose, although in combination with a PD-1-binding antibody. Although Bhattacharya et al and Long et al teach a combination with an anti-CTLA-4 antibody and another biotherapeutic, their teachings regarding anti-CTLA-4 in combination with another antibody is generally applicable and suggestive that it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that the dosing for the anti-CTLA4 antibody could also be reduced in other combinations of antibodies for the same reasons. Further, these lower doses must reasonably likely achieve comparable results as the full recommended therapeutic dose of the antibody alone, and one skilled in the art can determine these doses, meeting the limitations of claims 29 and 30. One skilled in the art, before the effective filing date of the instant application, would be motivated to reduce the dose of antibodies in combination therapies and have reasonable expectation of success that doing so may further minimize adverse side effects while still achieving therapeutic efficacy compared to monotherapies.
Claims 33, 35, 37-39, and new claim 46 depend on claim 22. The teachings of the references regarding claim 22 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim. Frendeus et al further teaches the method wherein the second antibody molecule is ipilimumab and/or tremelimumab (page 31, lines 17-19), arriving at all the limitations of claim 33.
Frendeus et al further teaches the method wherein the first antibody molecule either (i) lacks the Fc region, or (ii) has reduced binding to Fcy receptors via its Fc region, and has an aglycosylated Fc region (page 16, line 7 and page 17, line 1-2; page 38, Fig. 1C description), arriving at all the limitations of claim 35.
Frendeus et al further teaches the method wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin (page 15, lines 16-24), and the constant regions and the constant regions with the N297Q used throughout their human antibody examples are of human origin (page 16, line 4), arriving at all the limitations of claim 37.
Frendeus et al further teaches the method wherein the first antibody molecule comprises of the sequences as defined by claim 38. For example, antibody clone 1A01 comprises of CDRH1, CDRH2, and CDRH3 of sequences SEQ ID NO: 51, 52, 53, respectively, and CDRL1, CDRL2, CDRL3 of sequences SEQ ID NO: 54, 55, and 56, respectively (page 17), which have a 100% amino acid sequence match to the SEQ ID NO: 51-56, respectively, representing a VH CDR and VL CDR combination instantly claimed. Regarding new claim 46, Frendeus et al teaches the antibody clone 1A01 (page 17) which comprises of SEQ ID NO: 3 and SEQ ID NO: 27 for its VH sequence and VL sequence, respectively, which has a 100% identity match to the instant SEQ ID NO: 3 and SEQ ID NO: 27 (see Sequence Search Results), which is one possible embodiment for the VH and VL pairings from the instant claims.
Frendeus et al further teaches the method wherein the cancer is a FcyRIIb-positive B-cell cancer or is a FcyRIIb-negative cancer (Abstract; page 2-3 section: summary of the invention), arriving at all the limitations of claim 39.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Frendeus et al in view of Bhattacharya et al, and Long et al, as applied to claims 22, 24, 26, 27, 33, 35, 37-39 above, and further in view of Boutros et al (Boutros, C., et al, Safety profiles of anti-CTLA‑4 and anti‑PD‑1 antibodies alone and in combination, Nature Reviews Clinical Oncology, Vol 13, 08/2016 edition; published online 05/04/2016).
Claim 31 depends on claim 22. The teachings of the references regarding claim 22 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 31, Frendeus et al and Bhattacharya et al do not explicitly teach wherein use of the second antibody molecule at the lower dose either (i) improves tolerability of the second antibody molecule, or (ii) reduces side effects and/or reduces toxicity in the subject associated with the use of the second antibody molecule at the recommended therapeutic dose in the absence of the first antibody molecule.
However, Boutros et al teaches results of a clinical trial where ipilimumab (a CTLA-4 binding antibody) was given at 0.3 mg/kg, 3 mg/kg, and 10 mg/kg suggest the incidence of immune-related adverse effects (irAE) of any grade increases with higher doses of ipilimumab (page 478, column 2, paragraph 2). Boutros et al further teaches that irAE occurs in approximately 60-65% if patients treated with a moderate dose of ipilimumab (i.e. 3 mg/kg every 3 weeks for four cycles) (page 477, column 2, paragraph 3). Boutros et al further teaches that immune checkpoint inhibitors are different from other anticancer agents in that they target the immune system, and not the tumor (page 482, column 2, last paragraph), so their mechanism of action is linked to the mechanisms leading to irAE’s.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to reduce the likelihood of adverse effects from these antibodies by reducing the dose of the CTLA-4 binding antibody, in light of the teachings that increasing adverse effects is associated with increasing antibody dose. Especially because of the likely synergistic effects of the antibodies in a combination, as described previously, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that a lower dose in a combination therapy may achieve a similar therapeutic effect as a higher dose in a monotherapy, and this ability to use a lower dose can be leveraged to reduce adverse effects seen at higher doses of the anti-CTLA-4 antibody.
One skilled in the art, before the effective filing date of the instant application, would be motivated to reduce adverse drug effects, especially when using drugs, such as immune checkpoint inhibitors, that have a higher likelihood of inducing irAE’s than other anticancer drugs.
Although the teachings teach this association for the CTLA-4 binding antibody in a monotherapy, one skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that this likely holds for the antibody in a combination.
Claims 34, 45 are rejected under 35 U.S.C. 103 as being unpatentable over Frendeus et al in view of Bhattacharya et al, and Long et al, as applied to claims 22, 24, 26, 27, 33, 35, 37-39 above, and further in view of FDA YERVOY (FDA, Highlights of Prescribing Information for YERVOY (ipilimumab) injection, for intravenous use; published 07/2018).
Claims 28 and 34 depend on claim 22. Claim 45 depends on claim 28. The teachings of the references regarding claim 22 and 28 are incorporated in their entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 34, Frendeus et al and Bhattacharya et al do not explicitly teach the method wherein the dose of the second antibody molecule, which is the CTLA-4 binding antibody, is less than 10 mg/kg.
Regarding claim 45, Frendeus et al and Bhattacharya et al do not explicitly teach the method wherein the dose of the second antibody molecule is at least 50% lower than the maximum tolerated therapeutic dose.
However, Bhattacharya et al does teach that in formulations of only an anti-CTLA-4 antibody, the concentration of the anti-CTLA-4 antibody is 10 mg/ml to 200 mg/ml (page 3, line 32-33), whereas in a co-formulation comprising of the CTLA-4 antibody, the concentration of the antibody is 1 mg/ml to 100 mg/ml (page 6, line 35-36)), indicating a potentially lower dose when in combination compared to in monotherapies.
Regarding claim 34, FDA YERVOY teaches that dosing ipilimumab (a CTLA-4 binding human IgG1 with normal Fc-receptor binding) at 3 mg/kg every 3 weeks for unresectable or metastatic melanoma. Furthermore, when it is administered in combination with Nivolumab (a PD-1 binding antibody), the dose is reduced to 1 mg/kg (section: Dosage and Administration). Both doses are less than 10 mg/kg, meeting the limitations of claim 34.
Regarding claim 45, FDA YERVOY teaches that for adjuvant therapy for melanoma, ipilimumab is dosed at 10 mg/kg every 3 weeks. This means that the maximum tolerated dose of ipilimumab is at least 10 mg/kg. The dosing at 3 mg/kg or 1 mg/kg is therefore lower than the maximum tolerated dose of ipilimumab. If the maximum tolerated dose of the second antibody is at least 10 mg/ml, then the dose of 3 mg/kg or 1 mg/kg is at least 50% lower than the maximum tolerated therapeutic dose, meeting the limitations of claim 45.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that, at least for this CTLA-4-binding antibody, since it is therapeutically effective alone even at doses below 10 mg/kg, below its maximum therapeutic dose, and below 50% of its maximum therapeutic dose, it would also be effective in a co-formulation at these doses. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that even if this antibody doesn’t work better in combination than it does alone, it will still be therapeutically effective, even if the other drugs in the combination have no effect, assuming the other drugs, at least, do not antagonize it.
One skilled in the art, before the effective filing date of the instant application, would be motivated to use lower doses of drugs to minimize adverse effects, and especially so in combination therapies where there could be compounded drug effects.
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.
Application No. 18844583
Claims 1, 3, 6-19, 40-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 of copending Application No. 18844583 (App ‘583) in view of Frendeus et al (WO2019138005A2; published 07/18/2019), and Wei et al (Wei, S., et al, Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies, PNAS, vol. 116, no. 45; published 11/05/2019). Although the claims at issue are not identical, they are not patentably distinct from each other because of the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
App ‘583 claims 2, 3, and 5 recite a composition, a kit, and a method, respectively comprising of a first antibody that binds FcyRIIB via its Fab region and that lacks an Fc region or has reduced binding to Fcy receptors via the Fc region, and a second antibody molecule, wherein the second antibody molecule has an Fc region that binds to, or activates, at least one activating Fcy receptor, as is relevant to instant claims 1, 3, 6, 7, and their dependent claims. Claim 2 recites the composition for treating FcyRIIB-negative cancer in a patient, as is relevant to instant claims 1, 3, 6, 7, and their dependent claims. App ‘583 claims 2, 3, and 5 recite the second antibody binds to a receptor present on a tumor cells.
App ‘583 claims 31 and 32 depend on claim 3, which recites the kit, and further recites how the first antibody molecule is aglycosylated, as is relevant to instant claims 7.
App ‘583 claim 17 depends on claim 5, which recites the method, and further recites the first antibody molecule is a human, humanized, or of human origin antibody, or has an aglycosylated Fc region, as is relevant to claims 8, and 9.
App ‘583 claim 21 depends on claim 17, and further recites the IgG can be a list of aglycosylated antibodies of different origins, including human and murine, as is relevant to claim 9.
App ‘583 claim 6 depends on claim 5, and further recites the FcyRIIb-negative cancer is a solid cancer, as is relevant to instant claims 16-17.
App ‘583 claims 25, 26, and 28 teaches VH and VL sequences that match the combination of sequences encompassed by instant claims 10-15.
App ‘583 claims do not explicitly teach the second antibody specifically binds to PD-1 or PD-L1, or to CTLA-4, as is relevant to instant claims 1, 3, 6, 7, and their dependent claims. However, PD-L1 is a receptor present on tumor cells.
App ‘583 claims do not explicitly teach all three antibodies together in one combination, as is relevant to claims 1, 3, 6, 7, and dependent claims.
App ‘583 claims do not explicitly teach wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and/or an antibody molecule that specifically binds to CTLA-4, as is relevant to claims 1, 3, 6, 7, and dependent claims.
App ‘583 claims do not explicitly teach the cancer is relapsed and/or refractory cancer or that the second and/or third antibody is of human, humanized, or human origin, as is relevant to instant claims 18-19.
However, Frendeus et al teaches a combination comprising: an antibody molecule that specifically binds to FcyRIIb via its Fab region, and that lacks an Fc region or has reduced binding to Fcy receptors via its Fc region; and an antibody molecule that specifically binds to PD-1 or PD- L1, use in treating cancer in a patient (page 47, line 25 to page 48, line 11). Frendeus et al teaches a combination comprising: a first antibody molecule that specifically binds to FcyRllb via its Fab region, and that lacks an Fc region or has reduced binding to Fcy receptors via its Fc region; and an antibody molecule that specifically binds to CTLA-4 and that binds to at least one Fcy receptor via its Fc region (page 47, lines 4-23), for use in treating cancer in a patient. Together, these two combinations of two antibodies are relevant to claim 1. Frendeus et al further teaches these combinations in a method for treating cancer in a patient, the method comprising administering to the patient the combination of antibodies, as is relevant to claim 3 (page 47-48 and Abstract). Frendeus et al further teaches these combinations in a pharmaceutical composition, as is relevant to claim 6 (page 2, line 17-25; Abstract). Frendeus et al further teaches these combinations in a kit, as is relevant to claim 7 (page 2, line 26-34; Abstract).
Frendeus et al does not explicitly teach all three antibodies together in one combination, as is relevant to claims 1, 3, 6, 7, and dependent claims.
Frendeus et al does not explicitly teach wherein the cancer is resistant to treatment with an antibody molecule that specifically binds to PD-1 or PD-L1, and/or an antibody molecule that specifically binds to CTLA-4, as is relevant to claims 1, 3, 6, 7, and dependent claims.
Frendeus et al does not explicitly teach wherein the cancer is a relapsed and/or refractory cancer, as is relevant for claim 18.
However, Wei et al teaches a combination of full-length (Methods, paragraph 1) anti-CTLA-4 and anti-PD-1 blockade therapy has enhanced efficacy over monotherapy by both additive effects and combination therapy-specific effects (Abstract). Wei et al further teaches that these effect and mechanism differences may make combination therapy more efficacious in the less immunogenic tumor types refractory to monotherapies (Discussion, paragraph 2).
Although App ‘583 claims 2, 3, and 5 recite the second antibody binds to tumor cells, it would have been obvious, to one skilled in the art, with the application in view of the prior art before the effective filing date of the instant application, to substitute the second antibody with another anti-tumor agent that doesn’t necessarily bind tumor cells, such as checkpoint inhibitor antibodies that bind CTLA-4, to arrive at the instant limitation regarding an antibody molecule that specifically binds to CTLA-4 and that binds to at least one Fcy receptor via its Fc region. Furthermore, the motivation to combine teachings of combinations of two antibodies, to make a combination of three antibodies, arriving at all the claim limitations, is provided below.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to combine the prior art elements according to known methods to yield predictable results. In light of the teachings regarding all possible combinations of two antibodies using each of the three antibodies in the claims, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, to combine these combinations to arrive at the instant combination of all three antibodies, since each combination is shown to have enhanced efficacy over monotherapy. It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to apply the combination therapy of 3 antibodies to tumors refractory, and therefore, resistant, to monotherapies, considering the teachings of Wei et al regarding the enhanced effects of combination therapies compared to monotherapies of the same components.
One skilled in the art, before the effective filing date of the instant application, would be motivated to combine the three antibodies already taught in dual-antibody combination therapies because they all, generally but differently, work to remove negative regulations of immune cells. Frendeus et al already provides the motivation to combine antibodies binding FcyRIIB without an Fc region or reduced Fcy receptors binding via its Fc region with antibodies binding receptors on immune cells with Fcy receptor binding via its Fc region, specifically, immune checkpoint inhibitor antibodies binding CTLA-4 and PD-L1 (page 47-48). Wei et al then teaches the motivation to combine antibodies binding CTLA-4 and PD-L1. Furthermore, one skilled in the art, before the effective filing date of the instant application, would be motivated to apply these combinations towards tumors that were resistant or refractory to monotherapy treatment by anti-CTLA-4 and/or anti-PD1/PDL1 since the addition of the antibodies binding FcyRIIB with no or reduced Fcy receptor binding via a Fc region can augment these checkpoint inhibitors, as taught by FRENDEUS ET AL . These combinations could enable treatment tumors that should theoretically benefit from checkpoint inhibitors but could benefit from a secondary antibody that removes obstacles to their benefits.
Claims 8-19 depend on claim 3. Claim 40 depends on claim 17, which depends on claim 16, which depends on claim 3. The teachings of the references regarding the parent claims are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
FRENDEUS ET AL further teaches wherein the first antibody molecule lacks the Fc region or has an aglycosylated Fc region (Abstract), arriving at all the limitations of claim 8.
FRENDEUS ET AL further teaches wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin (page 15, lines 16-24), and the constant regions and the constant regions with the N297Q used throughout their human antibody examples are of human origin (page 16, line 4) arriving at all the limitations of claim 9.
FRENDEUS ET AL further teaches wherein the cancer is a FcyRIIb-positive B-cell cancer or is a FcyRIIb-negative cancer (Abstract; page 2-3 section: summary of the invention), arriving at all the limitations of claim 16, and further, wherein the FcyRIIb-negative cancer is a solid cancer (page 36, lines 6-7), arriving at all the limitations of claim 17. FRENDEUS ET AL further teaches combination methods specifically with CT26 and MC38 tumor models, which are both carcinomas (page 47), meeting the limitations of claim 40.
FRENDEUS ET AL further teaches wherein the anti-PD-1 or PD-L1 antibody and/or the anti-CTLA-4 antibody is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin (page 31, lines 1-9; and claims 28, 30, 31, and 32), arriving at all the limitations of claim 19.
FRENDEUS ET AL further teaches combinations of sequences for the first antibody molecules that arrive at the limitations of claims 10-15. For example, FRENDEUS ET AL teaches the antibody clone 1A01 (page 17) which comprises of SEQ ID NO: 3 and SEQ ID NO: 27 for its VH sequence and VL sequence, respectively, which has a 100% identity match to the instant SEQ ID NO: 3 and SEQ ID NO: 27 (see Sequence Search Results), which is one possible embodiment for the VH and VL pairings from the instant claims. This particular VH and VL pairing comprises of SEQ ID NO: 51-53, and 54-56 for its CDRH1-3 and CDRL1-3, respectively, which matches with the instant SEQ ID NO: 51-56 (see Sequence Search Results), which is one possible embodiment of CDR combinations from the instant claims. FRENDEUS ET AL teaches multiple other antibody clones that meet the instantly claimed sequence limitations for the first antibody molecule (page 17-30).
Claims 41-44 depend on claims 11 or 12. The teachings of the references regarding claim 11 or 12, as relevant, are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
FRENDEUS ET AL further teaches combinations of sequences for the first antibody molecules that arrive at the limitations of claims 41-44. For example, FRENDEUS ET AL teaches the antibody clone 1A01 (page 17), which, as described above, teaches VH and VL sequence pairings that would meet the limitations of claims 41-44.
Claims 22, 24, 26, 27, 29, 30, 33, 35, 37-39, and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 of copending Application No. 18844583 (App ‘583) in view of Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and further in view of Long et al (Long, G., et al, Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial, The Lancet Oncology, 18: 1202-10; published 07/17/2017). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The teachings of App ‘583 claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 are discussed above and incorporated here.
However, App ‘583 claims do not explicitly teach the second antibody is ipilimumab and/or tremelimumab, as is relevant to instant claim 33.
Furthermore, Frendeus et al teaches a method for treating cancer in a patient, the method comprising administering to the patient: a first antibody molecule that specifically binds to FcyRllb via its Fab region, and that lacks an Fc region or has reduced binding to Fcy receptors via its Fc region; and a second antibody molecule that specifically binds to CTLA-4 and that binds to at least one Fcy receptor via its Fc region; for use in treating cancer in a patient ((page 47, lines 4-23; claims 5, 30, 31), as is relevant to claims 22 and 26. Inherent to that method of treating is a combination comprising the antibodies; Frendeus et al also teaches a combination comprising: the first antibody molecule of claim 22; and the second antibody molecule of claim 22, as is relevant to claim 24 (page 47, lines 4-23). Frendeus et al further teaches this combination in a kit, as is relevant to claim 27 (page 47, lines 4-23).
Frendeus et al does not explicitly teach wherein the dose of the second antibody molecule that is administered is lower than the tolerated therapeutic dose, as is necessary for claims 22, 24, 26, and 27. Frendeus et al does not explicitly teach the dose of the second antibody is lower than the minimum therapeutic dose of the second antibody when administered alone, as is relevant to claim 29 or that the therapeutic effect of the first antibody and second antibody at the lower dose is comparable to the therapeutic effect of the second antibody molecule when administered alone at the recommended therapeutic dose of the second antibody, as is relevant to claim 30.
However, Frendeus et al does teach that lower doses of either antibody in the combination may be used and a physician could determine the dosage most suitable depending, in part, on the response of the particular patient and length of administration (page 33, lines 20-25).
Additionally, Bhattacharya et al also teaches formulations of ant-CTLA4 alone and in combination with anti-PD-1 antibodies to treat cancers (Abstract) and that these formulations may be administered with one or more additional biotherapeutic agents, suggesting anti-CTLA4 alone can be combined with other biotherapeutics (page 46, lines 12-14). Bhattacharya et al further teaches that dosage of the additional therapeutic agents in the combination should depend on achieving an acceptable level of side effects, as well as dose frequency, cancer severity, and individual patient’s response to the therapeutics (page 46, line 37 – page 47, line 17). Bhattacharya et al further teaches a preferred dose protocol is one involving the maximal dose or dose frequency that avoids significant undesirable side effects (page 47, lines 31-32).
Furthermore, Long et al, specifically teaches a reduced-dose ipilimumab (a CTLA-4-binding antibody) in combination with a standard-dose of another checkpoint inhibitor antibody for patients with advanced melanoma (page 1202, section: Interpretation).
In summary, Frendeus et al teaches the combination of the first and second antibodies as instantly claimed. Frendeus et al teaches lower doses of one or both antibodies is envisioned. Bhattacharya et al provides further rationale for lower doses of drugs in a combination. Long et al, specifically teaches reduced dose of the CTLA-4-binding antibody, although in combination with a PD-1-binding antibody. Although Bhattacharya et al and Long et al teach a combination with an anti-CTLA-4 antibody and another biotherapeutic, their teachings regarding anti-CTLA-4 in combination with another antibody is generally applicable and suggestive that it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that the dosing for the anti-CTLA4 antibody could also be reduced in other combinations of antibodies for the same reasons. Further, these lower doses must reasonably likely achieve comparable results as the full recommended therapeutic dose of the antibody alone, and one skilled in the art can determine these doses, meeting the limitations of claims 29 and 30. One skilled in the art, before the effective filing date of the instant application, would be motivated to reduce the dose of antibodies in combination therapies and have reasonable expectation of success that doing so may further minimize adverse side effects while still achieving therapeutic efficacy compared to monotherapies.
Claims 33, 35, 37-39, and new claim 46 depend on claim 22. The teachings of the references regarding claim 22 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim. Frendeus et al further teaches the method wherein the second antibody molecule is ipilimumab and/or tremelimumab (page 31, lines 17-19), arriving at all the limitations of claim 33.
Frendeus et al further teaches the method wherein the first antibody molecule either (i) lacks the Fc region, or (ii) has reduced binding to Fcy receptors via its Fc region, and has an aglycosylated Fc region (page 16, line 7 and page 17, line 1-2; page 38, Fig. 1C description), arriving at all the limitations of claim 35.
Frendeus et al further teaches the method wherein the first antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin (page 15, lines 16-24), and the constant regions and the constant regions with the N297Q used throughout their human antibody examples are of human origin (page 16, line 4), arriving at all the limitations of claim 37.
Frendeus et al further teaches the method wherein the first antibody molecule comprises of the sequences as defined by claim 38. For example, antibody clone 1A01 comprises of CDRH1, CDRH2, and CDRH3 of sequences SEQ ID NO: 51, 52, 53, respectively (page 17), which have a 100% amino acid sequence match to the SEQ ID NO: 51, 52, 53 representing a VH CDR combination instantly claimed. Regarding new claim 46, Frendeus et al teaches the antibody clone 1A01 (page 17) which comprises of SEQ ID NO: 3 and SEQ ID NO: 27 for its VH sequence and VL sequence, respectively, which has a 100% identity match to the instant SEQ ID NO: 3 and SEQ ID NO: 27 (see Sequence Search Results), which is one possible embodiment for the VH and VL pairings from the instant claims.
Frendeus et al further teaches the method wherein the cancer is a FcyRIIb-positive B-cell cancer or is a FcyRIIb-negative cancer (Abstract; page 2-3 section: summary of the invention), arriving at all the limitations of claim 39.
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 of copending Application No. 18844583 (App ‘583) in view of Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and further in view of Long et al, as applied to instant claims 22, 24, 26, 27, 33, 35, 37-39 above, and further in view of Boutros et al (Boutros, C., et al, Safety profiles of anti-CTLA‑4 and anti‑PD‑1 antibodies alone and in combination, Nature Reviews Clinical Oncology, Vol 13, 08/2016 edition; published online 05/04/2016). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 31 depend on claim 22. The teachings of the references regarding claim 22 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 31, Frendeus et al and Bhattacharya et al do not explicitly teach wherein use of the second antibody molecule at the lower dose either (i) improves tolerability of the second antibody molecule, or (ii) reduces side effects and/or reduces toxicity in the subject associated with the use of the second antibody molecule.
However, Boutros et al teaches results of a clinical trial where ipilimumab (a CTLA-4 binding antibody) was given at 0.3 mg/kg, 3 mg/kg, and 10 mg/kg suggest the incidence of immune-related adverse effects (irAE) of any grade increases with higher doses of ipilimumab (page 478, column 2, paragraph 2). Boutros et al further teaches that irAE occurs in approximately 60-65% if patients treated with a moderate dose of ipilimumab (i.e. 3 mg/kg every 3 weeks for four cycles) (page 477, column 2, paragraph 3). Boutros et al further teaches that immune checkpoint inhibitors are different from other anticancer agents in that they target the immune system, and not the tumor (page 482, column 2, last paragraph), so their mechanism of action is linked to the mechanisms leading to irAE’s.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to reduce the likelihood of adverse effects from these antibodies by reducing the dose of the CTLA-4 binding antibody, in light of the teachings that increasing adverse effects is associated with increasing antibody dose. Especially because of the likely synergistic effects of the antibodies in a combination, as described previously, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, that a lower dose in a combination therapy may achieve a similar therapeutic effect as a higher dose in a monotherapy, and this ability to use a lower dose can be leveraged to reduce adverse effects.
One skilled in the art, before the effective filing date of the instant application, would be motivated to reduce adverse drug effects, especially when using drugs, such as immune checkpoint inhibitors, that have a higher likelihood of inducing irAE’s than other anticancer drugs.
Although the teaching teach this association for the CTLA-4 binding antibody, one skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that this likely holds for the antibody in a combination.
Claims 28, 34, 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 of copending Application No. 18844583 (App ‘583) in view of Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and further in view of Long et, as applied to instant claims 22, 24, 26, 27, 33, 35, 37-39 above, and further in view of FDA YERVOY (FDA, Highlights of Prescribing Information for YERVOY (ipilimumab) injection, for intravenous use; published 07/2018). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 28 and 34 depend on claim 22. Claim 45 depends on claim 28. The teachings of the references regarding claim 22 and 28 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 28, Frendeus et al and Bhattacharya et al do not explicitly teach wherein use of the second antibody molecule is at a dose lower than the maximum tolerated therapeutic dose, nor, regarding claim 45, that it is at least 50% lower than the maximum tolerated therapeutic dose.
Regarding claim 34, Frendeus et al and Bhattacharya et al does not explicitly teach the method wherein the dose of the second antibody molecule, which is the CTLA-4 binding antibody, is less than 10 mg/kg.
However, Bhattacharya et al does teach that in formulations of only an anti-CTLA-4 antibody, the concentration of the anti-CTLA-4 antibody is 10 mg/ml to 200 mg/ml (page 3, line 32-33), whereas in a co-formulation comprising of the CTLA-4 antibody, the concentration of the antibody is 1 mg/ml to 100 mg/ml (page 6, line 35-36)), indicating a potentially lower dose when in combination compared to in monotherapies.
Regarding claim 34, FDA YERVOY teaches that dosing ipilimumab (a CTLA-4 binding human IgG1 with normal Fc-receptor binding) at 3 mg/kg every 3 weeks for unresectable or metastatic melanoma. Furthermore, when it is administered in combination with Nivolumab (a PD-1 binding antibody), the dose is reduced to 1 mg/kg (section: Dosage and Administration). Both doses are less than 10 mg/kg, meeting the limitations of claim 34.
Regarding claim 28, FDA YERVOY teaches that for adjuvant therapy for melanoma, ipilimumab is dosed at 10 mg/kg every 3 weeks. This means that the maximum tolerated dose of ipilimumab is at least 10 mg/kg. The dosing at 3 mg/kg or 1 mg/kg is therefore lower than the maximum tolerated dose of ipilimumab, meeting the limitations of claim 28.
Regarding claim 45, if the maximum tolerated dose is at least 10 mg/ml, then the dose of 3 mg/kg or 1 mg/kg is at least 50% lower than the maximum tolerated therapeutic dose, meeting the limitations of claim 45.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that, at least for this CTLA-4-binding antibody, since it is therapeutically effective alone even at doses below 10 mg/kg, below its maximum therapeutic dose, and below 50% of its maximum therapeutic dose, it would also be effective in a co-formulation at these doses. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that even if this antibody doesn’t work better in combination than it does alone, it will still be therapeutically effective, even if the other drugs in the combination have no effect, assuming the other drugs, at least, do not antagonize it.
One skilled in the art, before the effective filing date of the instant application, would be motivated to use lower doses of drugs to minimize adverse effects, and especially so in combination therapies where there could be compounded drug effects.
Application No. 19031514
Claims 1, 3, 6-19, 40-44 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 10-14, 17, 26-27, 37, 51 of copending Application No. 19031514 (App ‘514) in view of Frendeus et al (WO2019138005A2; published 07/18/2019), and further in view of Wei et al (Wei, S., et al, Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies, PNAS, vol. 116, no. 45; published 11/05/2019). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
App ‘514 claims 1, 3, and 4 recite a composition, a method of treating relapsed cancer and/or refractory cancer in a subject, and a kit, respectively, comprising of (i) an antibody molecule that specifically binds a cell surface antigen of a target cell, which antibody molecule has a Fc domain capable of binding FcyRIIb; (ii) and agent that prevents or reduces FcyRIIb binding to the Fc domain of the antibody, and optionally comprising of one or more therapeutic agent, as is relevant to instant claims 1, 3, 6, 7, and their dependent claims, except instant claim 17. App ‘514 claim 27, depending on the method of App ‘514 claim 3, further recites the agent is one or more antibody that specifically binds FcyRIIb and or which does not include a domain capable of recruiting an effector cell.
App ‘514 claim 27 further recites the agent that prevents or reduces FcyRIIb binding to the Fc domain of the antibody could lack an Fc region or be an antibody variant comprising a N297Q mutation, which leads to an agylcosylated murine Fc region, as discussed previously, as is relevant to instant claim 8.
App ‘514 claim 27 and 37 further recites the combination of VH, VL, and/or CDR sequences that the agent comprises of, matching with the combination of sequences recited in instant claims 10-15 and 41-44.
App ‘514 claim 3 recite the subject has target cells that express FcyRIIb and the method is used to treat relapsed and/or refractory cancer, which meet the limitations of instant claim 16 and 18, respectively.
App ‘514 claims do not explicitly recite the antibody molecule binds CTLA-4, nor that the agent that prevents or reduces FcyRIIb binding to the Fc domain of the antibody specifically binds to FcyRIIb via its Fab region and lacks an Fc region or has reduced binding to Fcy receptors via its Fc region, nor that the optional other therapeutic agent is an antibody that binds to PD-1 or PD-L1, as is relevant to instant claims 1, 3, 6, 7, and their dependent claims.
App ‘514 claims do not explicitly recite wherein the cancer is a FcyRllb-negative cancer, which is a solid cancer, as is relevant to claim 17.
App ‘514 claims do not explicitly recite the antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin, as is relevant to instant claim 19.
The teachings of the references regarding the combination of FcyRIIb-inhibiting agents and an anticancer agent with an Fc domain capable of binding Fcy receptors, the motivation and likelihood of success of combining specific antibodies and agents into a combination of three antibodies, their use in FcyRllb-negative cancer, and the motivation to use human, humanized, or human-originated antibodies are discussed in the previous double patenting discussion and incorporated here, as is relevant.
Claims 22, 24, 26, 27, 29, 30, 33, 35, 37-39, and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 10-14, 17, 26-27, 37, 51 of copending Application No. 19031514 (App ‘514) in view of Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and further in view of Long et al (Long, G., et al, Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial, The Lancet Oncology, 18: 1202-10; published 07/17/2017). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
App ‘514 claims 1, 3, and 4 recite a composition, a method of treating relapsed cancer and/or refractory cancer in a subject, and a kit, respectively, as discussed above, as is relevant to instant claims 22, 24, 26, 27, and their dependent claims.
App ‘514 claim 27 and 37 further recites the combination of VH, VL, and/or CDR sequences that the agent comprises of, matching with the combination of sequences recited in instant claim 38.
App ‘514 claim 3 recite the subject has target cells that express FcyRIIb and the method is used to treat relapsed and/or refractory cancer, which meet the limitations of instant claim 39.
App ‘514 claim 27 further recites the agent that prevents or reduces FcyRIIb binding to the Fc domain of the antibody could lack an Fc region or be an antibody variant comprising a N297Q mutation, which leads to an agylcosylated murine Fc region, as discussed previously, as is relevant to instant claim 35.
App ‘514 claims do not explicitly recite the antibody is ipilimumab and/or tremelimumab, as is relevant to instant claim 33.
App ‘514 claims do not explicitly recite the antibody molecule is selected from the group consisting of a human antibody molecule, a humanized antibody molecule, and an antibody molecule of human origin, as is relevant to instant claim 37.
Frendeus et al does not explicitly teach the dose of the second antibody is lower than the minimum therapeutic dose of the second antibody when administered alone, as is relevant to claim 29 or that the therapeutic effect of the first antibody and second antibody at the lower dose is comparable to the therapeutic effect of the second antibody molecule when administered alone at the recommended therapeutic dose of the second antibody, as is relevant to claim 30.
The teachings of the references regarding the antibody being ipilimumab and/or tremelimumab, and the motivation to use human, humanized, or human-originated antibodies are discussed in the previous double patenting discussion and incorporated here, as is relevant.
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 of copending Application No. 19031514 (App ‘514) in view of Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and further in view of Long et al, as applied to instant claims 22, 24, 26, 27, 33, 35, 37-39 above, and further in view of Boutros et al (Boutros, C., et al, Safety profiles of anti-CTLA‑4 and anti‑PD‑1 antibodies alone and in combination, Nature Reviews Clinical Oncology, Vol 13, 08/2016 edition; published online 05/04/2016). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 31 depend on claim 22. The teachings of the references regarding claim 22 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
App ‘514 claims do not explicitly recite the doses of the antibodies, as is relevant to instant claim 31.
The teachings of the references regarding the antibody the antibody dose is discussed in the previous double patenting discussion and incorporated here, as is relevant.
Claims 28, 34, 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 3, 5, 17, 21, 25, 26, 28, 31, 32 of copending Application No. 19031514 (App ‘514) in view of Frendeus et al (WO2019138005A2; published 07/18/2019) in view of Bhattacharya et al (WO2018204343Al; published 11/08/2018), and further in view of Long, as applied to instant claims 22, 24, 26, 27, 33, 35, 37-39 above, and further in view of FDA YERVOY (FDA, Highlights of Prescribing Information for YERVOY (ipilimumab) injection, for intravenous use; published 07/2018). Although the claims at issue are not identical, they are not patentably distinct from each other because the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 28, App ‘514 does not explicitly teach wherein use of the second antibody molecule is at a dose lower than the maximum tolerated therapeutic dose, nor, regarding claim 45, that it is at least 50% lower than the maximum tolerated therapeutic dose.
Regarding claim 34, App ‘514 does not explicitly teach the method wherein the dose of the second antibody molecule, which is the CTLA-4 binding antibody, is less than 10 mg/kg.
The teachings of the references regarding the antibody the antibody dose is discussed in the previous double patenting discussion and incorporated here, as is relevant.
Response to Arguments
35 USC § 112(a) - Written Description
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive. However, as noted in the Withdrawn Objections/Rejections section, the rejection has been withdrawn, but solely due to the Applicant’s amendments.
Regarding the lack of written description for the antibody’s CDR and VH/VL sequences combination:
Applicant argues that the Specification’s recitation of embodiments of the first antibody, providing the exact ordering and pairing of CDRs and VH/VL sequences, is sufficient to provide written description for the scope of the claims. Applicant argues that the claims provide the same ordered and paired sequences of CDRs and/or VH/VL from the specification.
The Examiner acknowledged and agrees that the Specification provided the exact ordering and pairing of CDRs and VH/VL sequences for distinct embodiments of the first antibody. However, the Examiner differs in the conclusion that this provides support for the scope of the previously presented claims because the scope of the claims encompassed more than these distinct embodiments. It was these other combinations encompassed by the claims, due to the lack of distinctly claiming the combinations and ordering, that lacked written description support. Further, these distinct embodiments do not amount to sufficient species to represent the genus of possible species encompassed by the claim because one antibody CDR sequence combination cannot be used to predict the function of other antibody CDR sequences, as explained in the rejection presented in the previous Action, due to the functional sensitivity to even small changes to the exact ordering, combination, and sequence of antibody CDRs.
The original claims did not distinctly claim ordered and paired sequences, as one cannot assume the order in which the sequences must be arranged by the order in which they are written and one cannot import limitations on the Claims from the Specification. Therefore, for example, a claim, as was previously presented, that recited “wherein the first antibody molecule comprises a variable light chain (VL) comprising the following CDRs: (i) SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56” was claiming all possible combinations of these three sequences as CDRL1, CDRL2, or CDRL3, amounting to 6 distinct permutations of SEQ ID NO: 54 and SEQ ID NO: 55 and SEQ ID NO: 56 for CDRL1, CDRL2, and CDRL3, wherein only one of the permutations has written description support. Similarly, claims that list VH and VL sequences cannot be interpreted to be limited to only the distinct pairings in the specification if the claims do not distinctly claim the pairings, and therefore these claims encompassed all possible combinations of a VH sequence with a VL sequence, of which only one had written support.
(B) Regarding the lack of written description for the comparison doses:
Applicant argues that definitions in the Specification were provided for each of dose terminology that the Office asserts is supposedly missing. Further, numbered embodiments 51 and 52 recite that the dose of the second antibody molecule is lower than the minimum effective therapeutic dose and that the therapeutic effect of the first and second antibody molecules used at the lower dose is comparable to the therapeutic effect of the second antibody molecule in the absence of the first antibody molecule at the maximum tolerated therapeutic dose.
The Examiner acknowledges such definitions were provided but despite these definitions, one skilled in the art does not know what these dose values are. The disclosure does not explicitly state the values of these doses. Even if some embodiments provide a comparison dose, without explicit disclosure of what this dose represents in the embodiment (i.e. whether it was the minimum therapeutic dose or the maximum therapeutic dose, or just a commonly used dose) one cannot assume what this comparison dose is.
Regarding the recited embodiments 51 and 52, the Arguments do not provide citations for where in the Specification these embodiments are but the Examiner assumes it is referring to page 100, paragraph (embodiments) 51 and 52. These are general statements similar to the claims. Just because something is stated, does not mean Applicant had possession of it. Further, as the Applicant notes, these are embodiments, and it is unclear which of their data falls within this embodiment. Is all the data presented so that the comparison dose of the anti-CTLA antibody is at the minimum therapeutic dose or the maximum tolerated therapeutic dose? If not, how would someone know what this dose is? The doses must be disclosed or art-recognized.
Finally, another disconnect between the arguments and the rejection seems to be regarding the scope of the claim. The arguments are directed towards the comparison dose when the anti-CTLA antibody is in a monotherapy, but the rejection is directed to the full scope of the claim which encompasses the comparison dose of the antibody derived from other combination therapies. This is why the amendments, which narrow the scope of the claims, overcome the rejection.
35 USC § 112(a) – Enablement
Applicant's arguments filed 07/06/2026 have been fully considered and are not found persuasive. However, as noted in the Withdrawn Objections/Rejections section, the rejection has been withdrawn, due to the Applicant’s amendments, which the Applicant’s arguments more suitably support.
Applicant argues that the dose limitations of claims 29-30 are read in the context of the defined FcγRIIb/CTLA-4 antibody combination, not as an abstract requirement to determine every possible dosing parameter for every antibody in isolation.
The Examiner understands the claim dependency and context provided by the parent claim, but the rejection was not directed towards the dosing parameter for every antibody in isolation, but rather to every possible dosing of the second antibody (i.e. the anti-CTLA-4 antibody), pursuant to the broadest reasonable interpretation of the claim scope. The previously presented claims simply recite the dose of the second antibody, which could be its dose as a monotherapy or its dose in combination therapy comprising of the anti-CTLA-4 antibody. The parent claim does not limit the type of therapy which this comparison dose comes from. Therefore, the parent claim only limits that the dose of the anti-CTLA-4 antibody in the combination with an anti-FcγRIIb antibody is less than the comparison dose, but provides no limiting context for the therapy that this comparison dose comes from.
The Applicant argues that working examples support their claims and argues: “For instance, in Example 3 and Figure 8, tumor-bearing mice were treated with anti-CTLA-4 antibody doses of 2 mg/kg or 0.4 mg/kg alone or in combination with FcyR-impaired anti-human FcyRIIb, with a 10 mg/kg anti-CTLA-4 dose serving as a maximally efficacious control.”
However, even though 0.4 mg/kg is the lowest dose the Applicant discloses testing, it is not explicitly stated nor inferable from the disclosure or art that this 0.4 mg/kg is the minimum therapeutic dose. Regarding the amended claims, the minimum therapeutic dose (or minimum effective dose) of the second antibody when administered alone for specific cancers is now enabled, because as the Applicant argues, this is routine and known in the art.
Applicant argues that the Specification provides substantial guidance for practicing the claimed dose limitations because it provides definitions of these doses and these definitions provide objective boundaries for the claimed dose comparisons and identify the relevant clinical criteria used by a skilled artisan. Further, the Specification explains how a skilled artisan would identify such doses for a given antibody, for example from the drug label or from doses of similar antibodies.
Firstly, a definition of the dose is not the same as knowing what the dose values are so that one is enabled to practice the invention without undue experimentation. One can know the definition of the minimum therapeutic dose and still not know what that dose is without data disclosed, in the art, or experimentally gathered. The disconnect between the arguments and the rejection seems to be regarding the scope of the claim. The arguments are directed towards determining the dose in a monotherapy, but the rejection is directed to the full scope of the claim which encompasses the comparison dose of the antibody derived from other combination therapies. This is why the amendments, which narrow the scope of the claims, overcome the rejection.
To address the arguments regarding the previously presented wider scope claims, the question of Enablement is not simply whether one understands how to arrive and identify the doses, but also whether they can use the invention without undue experimentation. As presented in the Enablement rejection in the previous Action, the Examiner acknowledges that the Specification provides definitions for the “minimum effective therapeutic dose” and “maximum tolerated therapeutic dose” in terms of their therapeutic effect. One understands them to be the minimum doses that leads to a measurable therapeutic effect, or the highest dose without unacceptable side effects, respectively. However, to be enabling of the claim, a person skilled in the art must know what the actual value of these doses are. However, these definitions do not themselves tell what the doses values are without experimentation. As summarized in the reason for withdrawing the rejection, the scope of the doses encompass doses for the antibody in monotherapies and combination therapies. Because of this, to be enabling for the full scope of this claimed invention, one needs to know the values of these claimed doses for the second antibody in combination therapies also. The values of these doses are not known in the art or disclosed and one cannot predict their exact values from monotherapy doses; therefore, one needs to determine the values of these doses themselves before they can use it as the maximum possible dose in the claimed invention. One may be able to hypothesize that the minimum therapeutic dose of the second antibody in an effective combination therapy may be lower than the minimum therapeutic dose of the second antibody in a monotherapy, but that does not help when the claims are claiming a dose that is lower than the minimum therapeutic dose.
To determine these doses in monotherapies, however, is routine in the art, and there are several ways to do it, as the Applicant argues.
Since the amendments sufficiently clarifies the scope of the claims to this enabled scope, the rejections are withdrawn.
35 USC § 103
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive.
Regarding claims 1, 3, 6-19, and 41-44:
Applicant argues that none of the cited references disclose the claimed combination of three antibodies. Applicant argues that, further, none of the cited references disclose the aforementioned three-antibody combination, and further for the treatment of cancer resistant to treatment by anti-PD-1/anti-PD-L1 and/or anti-CTLA-4 antibodies. Related to this, Applicant argues that a general teaching that two checkpoint inhibitors may be combined is not a reason to add a mechanistically distinct FcyRIIb-binding antibody to that dual checkpoint regimen.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The Examiner acknowledged that the references do not explicitly teach all three antibodies in one combination, but provided the explanation for why it would be obvious and motivated to combine the combinations of two antibodies taught by the references to arrive at the instant combination of three antibodies. Furthermore, some claims are directed to a combination of only two antibodies that are explicitly taught by Frendeus, and therefore Frendeus do read directly on these claims. See the teachings mapping in the chart below.
Finally, the art rejection is not going from two checkpoint inhibitors and adding the anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region, as the Applicant suggests. The art rejection starts with a base of the anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region with each of the claimed checkpoint inhibitors and provides direct motivation for why anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region are synergistic with checkpoint inhibitors, and further why it would be obvious to combine with multiple checkpoint inhibitors.
Anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region
Anti-CTLA-4
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Applicant further argues that the cited references do not disclose nor teach the three-antibody combination for use in treating a cancer that is resistant to treatment with an antibody that specifically binds PD-1, PD-L1, and/or CTLA-4. Applicant further argues that although Wei speculates the combination therapy may be useful in less immunogenic tumors, the instant disclosure actually tests the combination in treatment-resistant tumor models.
In response to applicant's argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Also, Applicant's argument relies on absolute predictability. MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required.
In this case, the motivation to use the combination of three antibodies is already established above, and as provided in the previous Office Action, Rejection Under 35 USC 103, paragraph 10, Wei et al further provides the motivation to use these antibodies in tumors refractory to monotherapies. A direct reduction to practice of this combination of antibodies in monotherapy treatment-refractory patients is not necessary to show obviousness when there is motivation provided by the prior art that would guide one skilled in the art towards this patient population. The likelihood of success is also provided in the previous Office Action, and incorporates the demonstrated efficacy of the combination therapy and the mechanism for why the addition of antibodies binding FcyRIIB with no or reduced Fcy receptor binding via a Fc region can logically augment these checkpoint inhibitors in monotherapy treatment-refractory patients.
Applicant further argues that the deficiencies of Frendeus is not cured by Wei because Wei only teaches a combination of anti-CTLA-4 plus anti-PD-1 therapy. Applicant further cites passages from Wei directed to the (1) the combination of anti-CTLA-4 and anti-PD-1 antibodies has enhanced efficacy but it is unclear by what mechanism such effects are mediated, (2) whether the combination therapy targets the same T cells as monotherapies, and (3) there are both additive and synergist effects between monotherapies observed in combination therapies, meaning the effect of the individual component in combination is at least as effective as it was as a monotherapy (Remarks, page 39, para. 2). Applicant further argues that cited passages from Wei reinforce the idea that a skilled artisan would not have been able to combine the alleged teachings of Wei and Frendeus to arrive at the claimed invention. Applicant cites passages from Wei directed to the need to investigate the mechanisms of action of combination therapies rather than indirectly inferring from the effects of monotherapies because pharmacodynamics and response for monotherapies may not accurately represent those of combination therapies (Remarks, page 30-30, para. 1).
Again, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The argument does not take into account the full teachings of Frendeus and Wei presented in the rejection. Frendeus teaches the combination of anti-CTLA-4 and an anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region. Frendeus teaches the combination of anti-PD-1and an anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region. The claims encompass a combination of three antibodies and Frendeus and Wei together teach all combinations of two antibodies that could be made from the three antibodies. Therefore, the predictability of the triple combination therapy is not merely based on the effects of each antibody monotherapy, but on the effects of each antibody in a dual combination therapy with each of the other two antibody in the triple combination therapy. Therefore, all possible two-way additive and/or synergistic effects are seen. It is reasonably likely, that knowing the monotherapy efficacy and two-way additive and synergistic effects, one skilled in the art can recognize that the triple therapy will be at least as effective as the dual therapy comprising of one checkpoint inhibitor and one antibody binding FcyRIIB with no or reduced Fcy receptor binding via a Fc region can augment these checkpoint inhibitors, which would be more effective than a monotherapy.
Applicant argues that their Specification shows unexpected therapeutic effect in a treatment-resistant tumor setting because the triple combination was therapeutically effective while the dual combination of anti-CTLA-4 and anti-PD-1 and the monotherapy of anti-PD-1 were not effective.
However, this is not an unexpected result, because the effect of the anti-FcRγIIB that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region on checkpoint inhibitors is known and disclosed in Frendeus. In fact, it is explicitly disclosed by Frendeus as prior art that they used an anti-FcyRIIB antibody without an Fc region or with reduced Fcy binding in order to prevent the counterproductive activation of Fcy receptors with the antibody’s Fc region while trying to block it with the Fab region. Frendeus already tells the effect of the anti-FcyRIIB antibody that lacks an Fc region or has reduced binding to Fcγ receptors via its Fc region. There is no unpredictability in how checkpoint inhibitors function in combination with this antibody.
Regarding claims 22, 24, 26 - 27, 33, 35, and 37 – 39:
Applicant argues that, in summary, the teachings of lowering anti-CTLA-4 doses both in a monotherapy and in combination therapy does not explicitly teach lowering the dose below the recommended therapeutic dose, and further does not teach lowering it in the specifically claimed combination therapy. Further, Applicant argues that because Long recites “an appropriately powered randomised trial” is needed to establish whether or not a reduced dose ipilimumab (an anti-CTLA-4 antibody) could sustain the desired response and do so at a comparable level as a full-dose ipilimumab. Applicant argues that because of this, the rejection relies on hindsight reasoning to teach the claimed lower dose.
First, whether the lower dose treatment is as effective as the full dose is not commensurate with the scope of the claim, as the claim does not require this effect. The claim simply requires a lower dose than the recommended therapeutic dose of the anti-CTLA-4 antibody in a monotherapy.
Long teaches the use of a reduced dose ipilimumab, which must be lower than the recommended therapeutic dose, in combination with another checkpoint inhibitor (anti-PD-1 antibody). Long provides the anti-tumor activity in the subject population using this reduced dose ipilimumab (Table 4). The motivation to combine the checkpoint inhibitors with the claimed FcγRIIb antibody has already been provided for the parent claim. Therefore, all the limitations of the claim are met by the combination of references. Additionally, the motivation to actually lower the dose, which is implicitly, in reference to the recommended therapeutic dose, because that would be the normal dose administered, is provided by Frendeus and Bhattacharya and relates to, amongst other things, the desire to lower side effects or toxicity and to cater the treatment to the disease severity and/or patient-specific responses.
Therefore, the rejection takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure; and as such, such a reconstruction is proper and does not amount to hindsight reasoning.
Furthermore, if only a powered randomized clinical trial in human subjects is sufficient to provide reasonable support for treatment, regardless of the results in humans with melanoma in a smaller trial, it should be noted that the instant disclosure also does not provide this level of support for its own claims, providing data only in mice and mice tumor models. MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required. This same benefit is also extended to the Applicant in reasonably extrapolating that their mice data extends to human cancer patients, and by this same threshold, the results in humans with melanoma in a small trial is treated as sufficient to provide reasonable expectation of the general effects of the treatment studied.
Regarding claim 31:
Applicant argues that the art only teaches a general dose-toxicity trend in an anti-CTLA-4 monotherapy, and not specific toxicity for the exactly claimed combination therapy. Applicant further cites Boutros "[d]ata providing formal comparisons of irAEs occurring at doses of 3 mg/kg versus 10 mg/kg of ipilimumab are still lacking" and uses that to undercut the teachings of the trend.
In response, MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required. In this case, it is reasonable to expect that if reducing the dose of anti-CTLA-4 in monotherapy reduces anti-CTLA-4-associated toxicity, then reducing it in combination therapies will also lead to reduced anti-CTLA-4-associated toxicities.
Also, in the comparison of irAEs that Applicant cited, Boutros is merely talking about a lack of comparison of the grades of the irAEs. However, Boutros then teaches that despite this lack of comparison the exact grades, the data is still suggestive of a dose-dependent toxicity trend where higher doses will lead to higher toxicities.
Regarding claim 28, 34, and 45:
Applicant’s argument is based on the erroneous statement that the Examiner asserts 10 mg/kg is the maximum tolerated dose.
However, as stated in the previous Office Action rejection, the Examiner notes that the maximum tolerated dose is at least 10 mg/kg and provides the logic for comparison from there and why the claimed dose of 3 mg/kg or 1 mg/kg must therefore meet the limitation of at least 50% lower than the maximum tolerated therapeutic dose.
Double Patenting
The applicant argues that the previous rejections did not teach the newly added limitations.
In response, the updated double patenting rejections provided above are updated to address the added limitations regarding the lower dose. The exact sequence matches were already taught for claim 38 in the specific CDR ordering claimed.
Conclusion
All claims are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/BONIRATH CHHAY/Examiner, Art Unit 1645 Wednesday, September 9, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 10, 2026
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