DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed January 23, 2026 is pending.
Claims 2-6, 9, 11, 12, 14-18, 21, 23, 25-28, 30-37, 40, and 42 are canceled.
Claims 1, 7, 8, 10, 13, 19, 20, 22, 24, 29, 38, 39, 41, and 43-45 are pending and currently under consideration.
Claim 1 is an independent claim.
In view of the applicant’s amendment filed January 23, 2026, the previous rejections under U.S.C. 112(b), U.S.C. 102, and nonstatutory double patenting as set forth in the Office Action mailed September 23, 2025 have been withdrawn the following objections and rejections are set forth.
Claim Rejections - 35 USC § 112
Indefinite Language
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 7-10, 13, 19, 20, 22, 24, 29, 38, 39, 41, and 43-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “said use” in line 12. However, there is no “use” recited prior to the recitation of “said use,” therefore this limitation lacks antecedent basis. Amending claim 1 to replace the phrase “said use” with the phrase “the method” would obviate this part of the rejection.
Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 7-10, 13, 19, 20, 22, 24, 29, 38, 39, 41, and 43-45 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a B7-H3-expressing cancer comprising administering a PD-1 x LAG-3 bispecific molecule comprising the CDRs of: DART-I from the instant specification, a PD-1 x LAG-3 bispecific molecule comprising SEQ ID NO:35, SEQ ID NO:39, SEQ IDS NO: 51, and SEQ ID NO: 55 (or humanized versions thereof) from the instant invention, or the PD-1 x LAG-3 bispecific molecules from WO 2015/200119, WO 2017/025498, WO 2018/083087, WO 2018/185043, WO 2018/134279, WO 2018/217940, and WO 2017/019846; and a B7-H3 binding molecule comprising the CDRs of: enoblituzumab, omburtamab, mirzotamab, BRCA84D, BRCA69D and PRCA157 (disclosed in WO2011109400), L7, L8, L11, M30, and M31 (disclosed in US2013/0078234), hmAb-C, and B7-H3 Antibody hmAb-D (disclosed in WO 2017/180813); does not reasonably provide enablement for a method of treating cancer comprising administering any PD-1 x LAG-3 bispecific molecule and any TA-binding molecule.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
In view of the Applicant’s election made 08/11/2025, the instant claims are drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
Nature of the invention/Breadth of the claims
Independent claim 1 is drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
Dependent claim 7 limits the PD-1 and LAG-3 bispecific molecule to an antibody.
Dependent claim 13 limits the PD-1 and LAG-3 bispecific molecule to an antibody comprising PD-1 VL Domain that comprises the amino acid sequence of SEQ ID NO:35, a PD-1 VH Domain that comprises the amino acid sequence of SEQ ID NO:39, a LAG-3 VL Domain that comprises the amino acid sequence of SEQ ID NO:51, and a LAG-3 VH Domain that comprises the amino acid sequence of SEQ ID NO:55.
Dependent claims 38, 39, and 41 limit the TA-binding molecule to a B7-H3-binding molecule comprising the LCDRs1-3 of SEQ ID NO: 71 and the HCDRs1-3 of SEQ ID NO: 76. Dependent claim 39 further limits the B7-H3-binding molecule to enoblituzumab.
State of the prior art/Predictability of the art
Antibody science is considered unpredictable. See Amgen v. Sanofi, 598 U.S. 594 (2023). The Supreme Court, citing Briney, B. et al. (Nature 2019; 566: 393-397, a reference of record), stated that the 26 anti-PCSK9 species that Amgen disclosed were not enough to represent the potential “quintillion” unique species claimed. The amino acid sequences of six CDRs (an antigen binding site) do not necessarily dictate binding and other desired function(s). For example, two anti-PCSK9 antibodies, one developed by Amgen and the other by Sanofi, have completely different CDR structures and yet their function is identical. Thus, functionally drawn claims, such as instant claim 1 reciting “a bispecific molecule that immunospecifically binds both PD-1 and LAG-3” and “a tumor antigen (TA) binding molecule” do not predict the structure necessary to have said function.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions), which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a protein having antigen-binding function. Proper association of heavy and light chain variable regions is required to form a functional antigen binding site (Almagro, J.C. & Fransson, J. Frontiers in Bioscience 2008; 13:1619-33, a reference of record).
In Amgen v. Sanofi, 598 U.S. 594 (2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies and disclosed two “trial and error” methods (“the roadmap” and “conservative substitution”) that Amgen insisted scientists could use to make other antibodies that perform these two functions. The case law applies to the instant claims which require a genus of bispecific PD1-LAG3-binding molecules and a genus of TA-binding molecules.
Thus, it would be unpredictable to one of ordinary skill in the art to make the genus of bispecific PD1-LAG3-binding molecules and the genus of TA-binding molecules encompassed by the claims and use them commensurate in scope with the breadth of the claims.
Working examples/Guidance in the specification
The specification provides several working examples of the claimed method which incorporates only one species of bispecific PD1-LAG3-binding molecule (DART-I) and only one species of TA-binding molecule (margetuximab, an anti-HER2 antibody).
The Applicant has also disclosed several PCT Publication Nos. that teach PD-1 x LAG-3 bispecific molecules for use in the treatment of cancer and/or a disease associated with a pathogen, including: WO 2015/200119, WO 2017/025498, WO 2018/083087, WO 2018/185043, WO 2018/134279, WO 2018/217940, WO 2017/019846 (e.g. see page 5, [0010] and Table 5 on page 55).
The specification further discloses many PD-1-Binding Domains and Molecules that can presumably be incorporated into the anti-PD-1 arm of the instantly claimed genus of PD-1 x LAG-3 bispecific molecules including PD-1-Binding Domains comprising the CDRs of the VL and VH Domains of SEQ ID NO:35 and SEQ ID NO:39 or the humanized VL and VH Domains of SEQ ID NO:36 and SEQ ID NO:39 (e.g. see page 40, [00132] – page 41, [0136]) and Table 1 (e.g. see pages 41-45). Similarly, the specification also discloses many LAG-3-Binding Domains and Molecules that can presumably be incorporated into the anti-LAG-3 arm of the instantly claimed genus of PD-1 x LAG-3 bispecific molecules including LAG-3-Binding Domains comprising the CDRs of the VL and VH Domains of SEQ ID NO:51 and SEQ ID NO:55 or the humanized VL and VH Domains of SEQ ID NO:51 and SEQ ID NO:55 (e.g. see page 46, [00146]) and Table 3 (e.g. see page 50).
Regarding the TA-binding molecules, the specification recites many such molecules in Table 7 which can be applied in the instantly claimed method (e.g. see pages 62-67). The specification states that the TA-binding molecules may also be ADCC-Enhanced versions that comprise the CDR Domains (or the VL and VH Domains) of any of the antibodies listed in Table 7 (e.g. see page 67, [00176]).
The specification further discloses that the TA-Binding molecule may be a HER2- Binding Molecule such as an antibody including margetuximab, trastuzumab, pertuzumab, and 8H11 (e.g. see page 67, [00177]). The heavy chain, light chain, VL, VH, and CDR amino acid sequences of margetuximab are recited on pages 69 and 70, [00181]-[00186].
The specification also discloses that the TA-Binding molecule may be a B7-H3-Binding Molecule such as an antibody including enoblituzumab, omburtamab, mirzotamab, BRCA84D, BRCA69D and PRCA157 (disclosed in WO2011109400), L7, L8, L11, M30, and M31 (disclosed in US2013/0078234), hmAb-C, and B7-H3 Antibody hmAb-D (disclosed in WO 2017/180813) (e.g. see page 68, [00178]).
Additional TA-Binding molecule contemplated by the Applicant include Obinutuzumab, BAT4306F, amivantamab, tafasitamab, and obexelimab (e.g. see [00199] spanning pages 72 and 73).
Amount of experimentation necessary
The instant specification discloses many bispecific PD1-LAG3-binding molecules and TA-binding molecules, yet, the claims are not limited to the use of these particular antibodies in treating cancer. The claimed methods encompass administering genera of bispecific PD1-LAG3-binding and TA-binding molecules without reciting any particular structure. There is insufficient objective evidence that the specific PD1-LAG3 bispecific molecules and TA-binding molecules disclosed in the specification can be extrapolated to provide guidance and direction for the claimed method of treating cancer by administering any PD-1 x LAG-3 bispecific molecule and any TA-binding molecule.
Thus, Based on the content of the disclosure in view of the recent Supreme Court ruling regarding nature of an antibody invention, a skilled artisan, through extensive trial-and-error experimentation, would have to make PD-1 x LAG-3 bispecific molecules, validate their function by demonstrating specific PD-1 and LAG-3 binding, and then use those in the claimed method of treating cancer with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
The instantly claimed TA-binding molecules are not enabled for the same reasons.
Given that the structure of a PD-1 x LAG-3 bispecific molecule and TA-binding molecule is essential to its function and the unpredictability in the art with respect to creating binding molecules, a person having ordinary skill in the art would have to perform undue experimentation in order to make the genera of PD-1 x LAG-3 bispecific and TA-binding molecules encompassed by the claims and use them commensurate in scope with the breadth of the claims.
Thus, the specification does not enable one of ordinary skill in the art to make and/or use what is claimed and therefore claims 1, 7-10, 13, 19, 20, 22, 24, 29, 38, 39, 41, and 43-45 are rejected under 35 U.S.C. 112(a).
Applicant's arguments filed January 23, 2026 have been fully considered but they are not persuasive.
The Applicant argues that the presently amended claims are enabled by the specification. The Applicant asserts that the specification describes that the dual inhibition of the PD-1/PD-L1 and LAG-3 checkpoint pathways can synergize with the anti-tumor activity or a TA-binding molecule, in particular, a TA-binding molecule having enhanced ADCC activity. The Applicant asserts that this synergy is demonstrated in Examples provided in the specification. The Applicant asserts that Example 2 shows cell studies where expression of the checkpoint inhibitors PD-1, PD-L1 and LAG-3 is upregulated for an ADCC-enhanced TA binding molecule (margetuximab) compared to an antibody binding the same epitope but having a wild-type Fc region (trastuzumab). The Applicant argues that thus, Example 2 shows that the upregulation of the checkpoint inhibitors PD-1, PD-L1 and LAG-3 is related to ADCC enhancement. The Applicant asserts that Example 3 shows synergy when a bispecific molecule that binds PD-1 and LAG-3 (DART I) is administered in combination with an ADCC-enhanced TA-binding molecule (margetuximab), but the effect is not seen when an antibody binding the same epitope but having a wild-type Fc region (trastuzumab) is used. The Applicant asserts that Example 4 provides early results from a clinical study showing a high response rate when administration of an ADCC-enhanced TA-binding molecule is combined with dual checkpoint inhibition of the PD-1/PD-L1 and LAG-3 checkpoint pathways.
The Applicant argues that the Office appears to agree that Applicant has demonstrated synergy between dual checkpoint inhibition of the PD-1/PD-L1 and LAG-3 pathways with a TA-binding molecule, however, the Office also alleges that the elected species of a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 does not include sufficient structural elements. Applicant respectfully disagrees.
The Applicant argues that the claims recite checkpoint inhibition using a bispecific binding molecule, or separate binding molecules, that immunospecifically bind the factors in the PD-1/PD-L1 and LAG-3 checkpoint pathways. The Applicant asserts that as demonstrated in Example 2, use of an ADCC-enhanced TA-binding molecule leads to upregulation of these factors. The Applicant asserts that a skilled person would thus expect that immunospecific binding of PD-1 or PD-L1 and LAG-3 would counteract this upregulation and lead to synergy with the TA-binding molecule.
The Applicant ultimately argues that for at least the above reasons, the current claims are enabled by the specification in view of the state of the art and that the rejection should be reconsidered and withdrawn.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that the presently amended claims are enabled by the specification and there is sufficient structural elements recited for the elected species of a bispecific molecule that immunospecifically binds both PD-1 and LAG-3; note instant specification discloses many bispecific PD1-LAG3-binding molecules and TA-binding molecules, yet, the claims are not limited to the use of these particular antibodies in treating cancer. The claimed methods encompass administering genera of bispecific PD1-LAG3-binding and TA-binding molecules without reciting any particular structure. There is insufficient objective evidence that the specific PD1-LAG3 bispecific molecules and TA-binding molecules disclosed in the specification can be extrapolated to provide guidance and direction for the claimed method of treating cancer by administering any PD-1 x LAG-3 bispecific molecule and any TA-binding molecule.
The art clearly teaches that all of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a protein having antigen-binding function (e.g. see Almagro, J.C. & Fransson, J. Frontiers in Bioscience 2008; 13:1619-33, a reference of record). Thus, based on the content of the disclosure in view of the recent Supreme Court ruling and the art regarding nature of an antibody invention, skilled artisan, through extensive trial-and-error experimentation, would have to make PD-1 x LAG-3 bispecific molecules, validate their function by demonstrating specific PD-1 and LAG-3 binding, and then use those in the claimed method of treating cancer with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed. Despite the large number of PD-1 x LAG-3 bispecific molecule species disclosed by the Applicant, these are not enough to represent the potential “quintillion” unique species encompassed by the genus of PD-1 x LAG-3 bispecific molecules as currently claimed. See Amgen v. Sanofi, 598 U.S. 594 (2023).
The instantly claimed TA-binding molecules are not enabled for the same reasons.
Given that the structure of a PD-1 x LAG-3 bispecific molecule and TA-binding molecule is essential to its function and the unpredictability in the art with respect to creating binding molecules, a person having ordinary skill in the art would have to perform undue experimentation in order to make the genera of PD-1 x LAG-3 bispecific and TA-binding molecules encompassed by the claims and use them commensurate in scope with the breadth of the claims.
Regarding the Applicants argument that the specification describes that the dual inhibition of the PD-1/PD-L1 and LAG-3 checkpoint pathways can synergize with the anti-tumor activity or a TA-binding molecule, in particular, a TA-binding molecule having enhanced ADCC activity and that this synergy is demonstrated in Examples provided in the specification; the Examiner agrees that the Applicant has disclosed a synergistic effect when a bispecific molecule that binds PD-1 and LAG-3 (DART I) is administered in combination with an ADCC-enhanced TA-binding molecule (margetuximab, an anti-HER2 antibody). However, the enablement rejection is not based on the ability of bispecific molecule that binds PD-1 and LAG-3 to synergize with a TA-binding molecule, the enablement rejection is based on the fact that the Applicant has not recited sufficient structure, namely a complete set of 6 CDRs in their proper order, which confer their function of binding their respective antigens.
In response to the Applicant’s arguments regarding the ADCC-enhanced Fc domain of the TA-binding molecule, again the enablement rejection is based on the fact that the Applicant has not recited sufficient structure, namely a complete set of 6 CDRs in their proper order, which confer their function of binding their respective antigens. This is not dependent on the structure of the Fc domain.
As such, the applicant’s argument has not been found persuasive.
Amending claim 1 to recite that the PD-1 x LAG-3 bispecific molecule comprises the CDRs of: DART-I from the instant specification, a PD-1 x LAG-3 bispecific molecule comprising SEQ ID NO:35, SEQ ID NO:39, SEQ IDS NO: 51, and SEQ ID NO: 55 (or humanized versions thereof) from the instant invention, or the PD-1 x LAG-3 bispecific molecules from WO 2015/200119, WO 2017/025498, WO 2018/083087, WO 2018/185043, WO 2018/134279, WO 2018/217940, and WO 2017/019846; and the B7-H3 binding molecule comprises the CDRs of: enoblituzumab, omburtamab, mirzotamab, BRCA84D, BRCA69D and PRCA157 (disclosed in WO2011109400), L7, L8, L11, M30, and M31 (disclosed in US2013/0078234), hmAb-C, and B7-H3 Antibody hmAb-D (disclosed in WO 2017/180813) would obviate this part of the rejection.
Claim Rejections - 35 USC § 103
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 7, 8, 10, 13, 19, 20, 22, 24, 29, 38, 39, and 43-45 are rejected under 35 U.S.C. 103 as being unpatentable Shah et al. 2017 (WO2017019846, an IDS reference filed October 19, 2022) in view of Rizvi et al. 2016 (JCO 34(15_suppl), TPS3104, a reference of record) and Pereira et al. 2018 (MABS; 10(5), 693-711, a reference of record).
In view of the elected species, independent claim 1 is drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
Dependent claim 7 limits the PD-1 and LAG-3 bispecific molecule to an antibody.
Dependent claims 8, 22, and 24 limit the method to that wherein the PD-L1 x LAG- 3 bispecific molecule is administered to said subject at a flat dose of from about 120 mg to about 800 mg. Dependent claim 22 limits the flat dose to about 300 mg or about 600 mg. Dependent claim 24 limits the flat dose to that which is administered once about every 2 weeks or about once about every 3 weeks.
Dependent claim 10 limits the ADCC-enhanced FC domain of the TA-binding molecule to that which comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose, and/or that comprises a bisecting O-GlcNAc.
Dependent claim 13 limits the PD-1 and LAG-3 bispecific molecule to an antibody comprising PD-1 VL Domain that comprises the amino acid sequence of SEQ ID NO:35, a PD-1 VH Domain that comprises the amino acid sequence of SEQ ID NO:39, a LAG-3 VL Domain that comprises the amino acid sequence of SEQ ID NO:51, and a LAG-3 VH Domain that comprises the amino acid sequence of SEQ ID NO:55.
Dependent claims 19 and 20 limit the method to that wherein said method comprises administering a PD-1 x LAG-3 bispecific molecule that comprises an Fc Region and a Hinge Domain to said subject, wherein said Fc Region is a variant Fc Region that comprises one or more amino acid modifications that reduces the affinity of the variant Fc Region for an FcyR. Claim 20 limits the modifications to those that enhance the serum half-life of the variant Fc Region and comprise the substitution of M252Y, S254T and T256E.
Dependent claim 29 limits the B7-H3-expressing cancer to a hematological malignancy.
Dependent claims 38 and 39 limit the TA-binding molecule to a B7-H3-binding molecule comprising the LCDRs1-3 of SEQ ID NO: 71 and the HCDRs1-3 of SEQ ID NO: 76. Dependent claim 39 further limits the B7-H3-binding molecule to enoblituzumab and the method to that wherein enoblituzumab is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks.
Dependent claim 43 limits the method to that wherein cells expressing LAG- 3 are present in a biopsy of said cancer prior to said treatment.
Dependent claim 44 limits the method to that wherein cells expressing PD-1 are present in a biopsy of said cancer prior to said treatment.
Dependent claim 45 limits the method to that wherein PD-L1 expression on the surface of cells of said cancer, prior to said treatment, is less than 1% as determined using a Combined Positive Score (CPS) or a Tumor Proportion Score (TPS).
Regarding claims 1, Shah et al. teach a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) (e.g. see claim 10) which is used in the treatment of cancer (e.g. see claim 23). Shah et al. also teach that the anti-PD-1-binding molecules of their invention, including the PD-1 x LAG-3 bispecific molecules of claim 10, can be combined with other anticancer agents, in particular, molecules that specifically bind a cancer antigen (e.g., antibodies, diabodies) including those that bind B7-H3 (e.g. see [0003], [00396], and [00397]).
Regarding claim 7, Shah et al. also teach that their PD-1 x LAG-3 bispecific molecule is a diabody or a bispecific antibody (e.g. see claim 11).
Regarding claim 13, Shah et al. specifically teach the PD-1 x LAG-3 bispecific molecule DART (Dual Affinity Re-Targeting Reagents) J, a bispecific, four chain diabody having two binding sites specific for PD-1 and two binding sites specific for LAG-3 (e.g. see [00331]). The PD-1 binding site of DART J comprises a VH Domain of a monoclonal antibody capable of binding PD-1 (VHPD-I hPD-1 mAb 7 VH1) (SEQ ID NO:147) and a VL Domain of a monoclonal antibody capable of binding to PD-1 (VLPD-I hPD-1 mAb 7 VL2) (SEQ ID NO:153) (e.g. see [00331] and [00333]). The LAG-3 binding site of DART J comprises a VH Domain of a monoclonal antibody capable of binding to LAG-3 (VHLAG-3 hLAG-3 mAb 6 VH1) (SEQ ID NO: 294) and a VL Domain of a monoclonal antibody capable of binding to LAG-3 (VLLAG-3 hLAG-3 mAb 6 VL1) (SEQ ID NO:296) (e.g. see [00331] and [00333]). These VH and VL domains are identical to those recited in claim 13. See sequence alignments below.
Regarding claim 19, Shah et al. also teach that their PD-1 x LAG-3 bispecific molecule comprises an Fc region and a hinge domain, wherein said Fc Region is a variant Fc Region that comprises one or more amino acid modifications that reduces the affinity of the variant Fc Region for an FcyR and/or enhances the serum half-life of the variant Fc Region (e.g. see claims 13, 15, and 18).
Regarding claim 20, Shah et al. also teach that the modifications that reduces the affinity of the variant Fc Region for an FcyR comprise the substitution of L234A and/or L235A and the one or more amino acid modifications that enhances the serum half-life of the variant Fc Region wherein said modifications that that enhances the serum half-life of the variant Fc Region comprise the substitution of M252Y, S254T and T256E, wherein said numbering is that of the EU index as in Kabat (e.g. see claims 19 and 20).
Regarding claim 29, Shah et al. also teach that the cancer may be a hematological malignancy (e.g. see claims 25 and 26).
Shah et al. also teach that the PD-1 x LAG-3 bispecific binding molecules of their invention are intended to coordinately bind to two different epitopes: an epitope of PD-1 and an epitope of LAG-3, so as to attenuate the inhibitory activities of such molecules (e.g. see [00281]). PD-1 and LAG-3 are both immune check point regulatory molecules and by binding them immune system inhibition is blocked (e.g. see [00392]). In particular, the PD-1 x LAG-3 bispecific binding molecules are useful for augmenting T-cell mediated immune response in a subject. Specifically, PD-1 x LAG-3 bispecific binding molecules can be used to treat any disease or condition associated with an undesirably suppressed immune system, including cancer, by reducing or eliminating the inhibitory effects transduced by PD-1 and LAG-3 in T-cells and reinvigorating the T-cell population for tumor cell toxicity (e.g. see [00392]).
Alignment of Shah et al. SEQ ID NO: 147 and instant SEQ ID NO: 39 (PD-1 VH domain):
Query Match 100.0%; Score 634; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSETWL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSETWL 60
Qy 61 DQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSS 119
Alignment of Shah et al. SEQ ID NO: 153 and instant SEQ ID NO: 35 (PD-1 VL domain):
Query Match 100.0%; Score 578; DB 1; Length 111;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQKPGQPPKLLIHAASNQGS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQKPGQPPKLLIHAASNQGS 60
Qy 61 GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPYTFGGGTKVEIK 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPYTFGGGTKVEIK 111
Alignment of Shah et al. SEQ ID NO: 294 and instant SEQ ID NO: 55 (LAG-3 VH domain):
Query Match 100.0%; Score 632; DB 1; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNMDWVRQAPGQGLEWMGDINPDNGVTIY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNMDWVRQAPGQGLEWMGDINPDNGVTIY 60
Qy 61 NQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREADYFYFDYWGQGTTLTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREADYFYFDYWGQGTTLTVSS 118
Alignment of Shah et al. SEQ ID NO: 296 and instant SEQ ID NO: 51 (LAG-3 VL domain):
Query Match 100.0%; Score 562; DB 1; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDVSSVVAWYQQKPGKAPKLLIYSASYRYTGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVSSVVAWYQQKPGKAPKLLIYSASYRYTGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSTPWTFGGGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSTPWTFGGGTKLEIK 107
Regarding claims 1, 10, 38, and 39, Shah et al. do not teach that the TA-binding molecule comprises an ADCC-enhanced Fc domain (claim 1), wherein said ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose (claim 10); or that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab (claim 38) or that it is enoblituzumab and is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks (claim 39).
Rizvi et al. teach that enoblituzumab is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family (e.g. see lines 1 and 2 under “Background”). B7-H3 has limited expression in normal tissue but high expression in many cancers including melanoma (M), squamous cell cancer of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC) (e.g. see lines 4-6 under “Background”). B7-H3 overexpression correlates with poor prognosis in a broad range of cancers suggesting a potential role in enabling tumor immune escape (e.g. see lines 6-7 under “Background”). Rizvi et al. also teach that the hypotheses for combining enoblituzumab with pembrolizumab, an anti-PD-1 antibody, are: 1) immune-modulating agent combinations may mediate additive or synergistic antitumor activity and in tumors where neither single agent alone has substantial anti-tumor effect, 2) engagement of both innate and adaptive immunity, 3) targeting both B7-H3 and PD-1 may enhance the immune response against tumors via modulation of T-cell immunosuppression, 4) limited expression of B7-H3 on normal tissues may limit the risk of auto-immune related adverse events; thus enoblituzumab may be combined more readily with immune-modulating agents (e.g. see lines 8-15 under “Background”).
Pereira et al. teach that antibody dependent cellular cytotoxicity (ADCC) is a critical effector function triggered when a therapeutic antibody is used to eliminate target cells (e.g. see page 706, paragraph spanning the left and right columns). It is well-known that ADCC is modulated by the N-linked glycosylation in the Fc region of the antibody (e.g. see Abstract). In particular, the absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells, such as natural killer cells, which leads to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy (e.g. see Abstract).
Pereira et al. also teach that various approaches have been utilized to target the fucosylation machinery of the host cell lines or more economically effective approaches that involve glycoengineering mammalian cell lines to produce afucosylated antibodies have also been applied to achieve this goal (e.g. see page 706, right column, second paragraph). Many glycoengineered antibodies, with their Fc core fucose partially or completely removed, have been investigated in animal models and a number of them have been studied in clinical trials with several approved for use in clinical practice. It is expected that more afucosylated antibodies will enter clinical trials and subsequently be approved for clinical use (e.g. see page 706, right column, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Shah et al. to incorporate the teachings of Rizvi et al. and Pereira et al. to include that the TA-binding molecule comprises an ADCC-enhanced Fc domain comprising an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose and that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab and is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks. This is because enoblituzumab, an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3, is expected to have additive or synergistic antitumor activity when combined with the immune checkpoint anti-PD-1 antibody, pembrolizumab in treating a B7-H3-expressing cancer (Rizvi et al.).
Enoblituzumab is Fc optimized to enhance binding to the activating FcγR (Rizvi et al.). It is well known that ADCC is a critical effector function triggered by a therapeutic antibody to eliminate target cells (Pereira et al.). ADCC is mediated by binding of the antibody Fc domain to an activating FcγR which is modulated by the N-linked glycosylation in the Fc region of the antibody (Pereira et al.). It is also well known that the absence of core fucose on the Fc N-glycan increases antibody binding affinity to activating FcγR leading to enhanced ADCC activity (Pereira et al.). Thus, it is desirable to design therapeutic antibodies with enhanced ADCC activity, such as those lacking core fucose, in order to improve their ability to eliminate target cells (Pereira et al.).
Given the limited expression of B7-H3 in normal tissue and its high expression in many cancers, the potential of targeting B7-H3 for treating B7-H3-expressing cancers, the expected synergistic effect of combining the anti-B7-H3 antibody enoblituzumab with an immune checkpoint inhibitory molecule for treating B7-H3-expressing cancer, that the Fc of enoblituzumab is optimized to enhance binding to the activating FcγR, and that glycoengineered therapeutic antibodies have been designed to eliminate core fucose on the Fc N-glycan to increase its binding affinity for FcγRIIIa and enhance their ADCC activity; it would have been obvious to a skilled artisan to have included that Shah et al.’s TA-binding molecule comprises an ADCC-enhanced Fc domain comprising an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose and that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab with a reasonable expectation of success.
Given that enoblituzumab is expected to have a synergistic anti-tumor effect when combined with a monospecific immune check point inhibitory molecule, namely an anti-PD-1 antibody; a skilled artisan would have reasonably expected that the combination of enoblituzumab with a bispecific immune check point inhibitory molecule, i.e. Shah et al.’s PD-1 x LAG-3 bispecific molecules, would at least have the same degree of synergy, if not more, as that described by Rizvi et al. for enhanced killing of B7-H3-expressing tumors. Shah et al.’s PD-1 x LAG-3 bispecific molecules are intended to coordinately bind to and inhibit two immune check point regulatory molecules. The PD-1 x LAG-3 bispecific molecules are expected to reduce or eliminate the inhibitory effects transduced by PD-1 and LAG-3 in T-cells thereby reinvigorating the T-cell population for enhanced anti-tumor cytotoxicity. Therefore, a skilled artisan would have reasonably expected that the immune checkpoint inhibition by Shah et al.’s PD-1 x LAG-3 bispecific molecules would be done twice over when compared to Rizvi et al.’s monospecific immune check point inhibitory molecule. This would have been especially obvious to a skilled artisan because the combination therapy taught by both Shah et al. and Rizvi et al. is intended to enhance the immune response against tumors via modulation of T-cell immunosuppression by the immune checkpoint inhibitory molecules.
Furthermore, a skilled artisan would reasonably expect an afucosylated enoblituzumab to have enhanced ADCC function and, in turn, an enhanced ability to eliminate target cells especially when used in combination with a molecule that reinvigorates the T-cell population for enhanced anti-tumor cytotoxicity. Taken together, a skilled artisan would have reasonably expected that the combination of afucosylated enoblituzumab with an immune checkpoint inhibitory PD-1xLAG-3 bispecific molecule would improve the method of treating cancer by combining a PD-1xLAG-3 bispecific molecule and a TA-binding molecule as taught by Shah et al.
Regarding claims 8, 22, and 24 and further regarding claim 39, which recite that the PD-1 x LAG-3 bispecific molecule is administered as “a flat dose of from about 120 mg to about 800 mg,” “a flat dose of from about 300 mg or at a flat dose of about 600 mg,” “said flat dose is administered once about every 2 weeks or about once about every 3 weeks,” and “administering enoblituzumab at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks,” respectively; determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages, and like factors are well within the knowledge and expertise of the medical practitioner. It would have been obvious to one of ordinary skill in the art at the time the Applicant’s invention was filed, to determine all operable and optimal intervals of treatment because optimal intervals are an art-recognized, result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between the Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all of the various permutations of interval ranges as claimed in instant claims 8, 22, 24, and 39, it would be conventional and within the skill of the art to identify the optimal intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II A.
Regarding claims 43-45 which recite limitations drawn to the protein expression profile of the cancer cells prior to treatment, specifically the expression of LAG-3 (claim 43) and PD-1 (claim 44) in biopsied samples, and PD-L1 expression on the surface of the cancer cells (claim 45), these limitations do recite active steps of the instantly claimed method of treating cancer with a PD-1xLAG-3 bispecific molecule in a subject in need thereof. Thus, the PD-1xLAG-3 bispecific molecules taught by Shah et al. would necessarily bind to cells expressing the recited antigens and where these antigens are not expressed the claimed PD-1xLAG-3 bispecific molecules would not bind. Furthermore, as it is understood by the Examiner, given the content of the disclosure, the claimed PD-1xLAG-3 bispecific molecules are intended to antagonize PD-1 and LAG-3 expressed on T-cells, particularly those T-cells present in the tumor microenvironment (TME). The PD-1xLAG-3 bispecific molecules are intended to eliminate the inhibitory signals transduced by engagement of these immune check point regulators, thereby reinvigorating the anti-cancer activity of these T-cells. Thus, given that it is well-known that T-cells enter the TME, where they are known as tumor infiltrating lymphocytes (TILs), the TME of the tumors recited by Shah et al. would necessarily include TILs that express PD-1 and LAG-3 to which the PD-1xLAG-3 bispecific molecules could bind.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant's arguments filed January 23, 2026 have been fully considered but they are not persuasive.
The Applicant argues that there is no disclosure in Shah that would provide a reason to treat a B7-H3 cancer with an ADCC-enhanced TA-binding molecule in combination with the claimed dual checkpoint inhibition. The Applicant asserts that Shah discloses a bispecific binding molecule that binds PD-1 along with a second epitope. The Applicant asserts that Shah also discloses that the second epitope can be either B7-H3 or LAG-3. The Applicant argues that there is no suggestion in Shah of combining dual PD-1/PD-L1 and LAG-3 binding molecules with a B7-H3 binding molecule. The Applicant asserts that, further, it was the current inventors who discovered that dual checkpoint inhibition is synergistic with administration of a TA-binding molecule having enhanced ADCC activity, as described above. The Applicant asserts that there is no suggestion in Shah that such a synergistic effect could be achieved.
The Applicant further argues that Pereira does not provide a reason to modify Shah as suggested by the Office. The Applicant asserts that Pereira generally discusses ADCC as an effector function. The Applicant argues that the combination of Shah and Pereira would not have led a POSA to a combination of dual PD-1/PD-L1 checkpoint inhibition and an ADCC- enhanced TA-binding molecule as currently claimed.
The Applicant also argues that Rizvi does not suggest combining dual checkpoint inhibition with targeting of B7-H3 and, thus, a POSA reading Shah and Rizvi would not have had a reason to modify the teachings of Shah, but instead would have considered the best strategy to be administration of one or more binding molecules that bind PD-1 and B7-H3.
It is noted that Applicant’s arguments with respect to Bang et al. 2017 (Ann. Oncol.; 28(4), 855-861, a reference of record) have been considered but are moot because the new grounds of rejection do not rely on the teachings of Bang et al. as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s argument that no suggestion in Shah of combining dual PD-1/PD-L1 and LAG-3 binding molecules with a B7-H3 binding molecule; note that Shah et al. teach that the anti-PD-1-binding molecules of their invention, including the PD-1 x LAG-3 bispecific molecule, can be combined with other anticancer agents, in particular, molecules that specifically bind a cancer antigen (e.g., antibodies, diabodies) including those that bind B7-H3 (e.g. see [0003], [00396], and [00397]).
Regarding the Applicant’s arguments that (1) there is no disclosure in Shah that would provide a reason to treat a B7-H3 cancer with an ADCC-enhanced TA-binding molecule in combination with the claimed dual checkpoint inhibition and (2) there is no suggestion in Shah that such a synergistic effect could be achieved with administration of a TA-binding molecule having enhanced ADCC activity and a molecule with dual checkpoint inhibition (i.e. PD-1 x LAG-3 bispecific molecule); the Examiner agrees that Shah et al. alone do not teach a reason to treat a B7-H3 cancer with an ADCC-enhanced TA-binding molecule in combination with the claimed dual checkpoint inhibition or its synergistic effect.
However, as stated above, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Shah et al. to incorporate the teachings of Rizvi et al. and Pereira et al. to include that the TA-binding molecule comprises an ADCC-enhanced Fc domain comprising an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose and that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab. This is because enoblituzumab, an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3, is expected to have additive or synergistic antitumor activity when combined with the immune checkpoint anti-PD-1 antibody, pembrolizumab in treating a B7-H3-expressing cancer (Rizvi et al.). The Fc of enoblituzumab is optimized to enhance binding to the activating FcγR, expectedly, leading to enhanced ADCC activity (Rizvi et al. and Pereira et al.).
Given the limited expression of B7-H3 in normal tissue and its high expression in many cancers, the potential of targeting B7-H3 for treating B7-H3-expressing cancers, the expected synergistic effect of combining the anti-B7-H3 antibody enoblituzumab with an immune checkpoint inhibitory molecule for treating B7-H3-expressing cancer, that the Fc of enoblituzumab is optimized to enhance binding to the activating FcγR, and that glycoengineered therapeutic antibodies have been designed to eliminate core fucose on the Fc N-glycan to increase its binding affinity for FcγRIIIa and enhance their ADCC activity; it would have been obvious to a skilled artisan to have included that Shah et al.’s TA-binding molecule comprises an ADCC-enhanced Fc domain comprising an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose and that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab with a reasonable expectation of success.
Given that enoblituzumab is expected to have a synergistic anti-tumor effect when combined with a monospecific immune check point inhibitory molecule, namely an anti-PD-1 antibody; a skilled artisan would have reasonably expected that the combination of enoblituzumab with a bispecific immune check point inhibitory molecule, i.e. Shah et al.’s PD-1 x LAG-3 bispecific molecules, would at least have the same degree of synergy, if not more, as that described by Rizvi et al. for enhanced killing of B7-H3-expressing tumors. Shah et al.’s PD-1 x LAG-3 bispecific molecules are intended to coordinately bind to and inhibit two immune check point regulatory molecules. The PD-1 x LAG-3 bispecific molecules are expected to reduce or eliminate the inhibitory effects transduced by PD-1 and LAG-3 in T-cells thereby reinvigorating the T-cell population for enhanced anti-tumor cytotoxicity. Therefore, a skilled artisan would have reasonably expected that the immune checkpoint inhibition by Shah et al.’s PD-1 x LAG-3 bispecific molecules would be done twice over when compared to Rizvi et al.’s monospecific immune check point inhibitory molecule. This would have been especially obvious to a skilled artisan because the combination therapy taught by both Shah et al. and Rizvi et al. is intended to enhance the immune response against tumors via modulation of T-cell immunosuppression by the immune checkpoint inhibitory molecules.
Furthermore, a skilled artisan would reasonably expect an afucosylated enoblituzumab to have enhanced ADCC function and, in turn, an enhanced ability to eliminate target cells especially when used in combination with a molecule that reinvigorates the T-cell population for enhanced anti-tumor cytotoxicity. Taken together, a skilled artisan would have reasonably expected that the combination of afucosylated enoblituzumab with an immune checkpoint inhibitory PD-1xLAG-3 bispecific molecule would improve the method of treating cancer by combining a PD-1xLAG-3 bispecific molecule and a TA-binding molecule as taught by Shah et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Regarding the Applicant’s argument that Pereira does not provide a reason to modify Shah and that the combination of Shah and Pereira would not have led a POSA to a combination of dual PD-1/PD-L1 checkpoint inhibition and an ADCC-enhanced TA-binding molecule as currently claimed; note that it is well known that ADCC is a critical effector function that is mediated by the Fc domain of the antibody (Pereira et al.). ADCC can be modulated by the N-linked glycan in the Fc region of an antibody (Pereira et al.). Afucosylation of the Fc N-glycan increases IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells, such as natural killer cells, which in turn leads to enhanced ADCC activity (Pereira et al.). Therefore, given that importance of ADCC in eliminating tumor cells and that glycoengineered therapeutic antibodies have been designed to eliminate core fucose on the Fc N-glycan to increase its binding affinity for FcγRIIIa and enhance its ADCC activity and therapeutic efficacy; it would have been obvious to a skilled artisan to experiment with removing the core fucose from the Fc N-glycan of Shah et al.’s TA-binding antibody in order to enhance its ADCC with a reasonable expectation of success.
Regarding the Applicant’s argument that Rizvi does not suggest combining dual checkpoint inhibition with targeting of B7-H3 and, thus, a POSA reading Shah and Rizvi would not have had a reason to modify the teachings of Shah, but instead would have considered the best strategy to be administration of one or more binding molecules that bind PD-1 and B7-H3; note that given that enoblituzumab is expected to have a synergistic anti-tumor effect when combined with a monospecific immune check point inhibitory molecule, namely an anti-PD-1 antibody; a skilled artisan would have reasonably expected that the combination of enoblituzumab with a bispecific immune check point inhibitory molecule, i.e. Shah et al.’s PD-1 x LAG-3 bispecific molecules, would at least have the same degree of synergy, if not more, as that described by Rizvi et al. for enhanced killing of B7-H3-expressing tumors. Shah et al.’s PD-1 x LAG-3 bispecific molecules are intended to coordinately bind to and inhibit two immune check point regulatory molecules. The PD-1 x LAG-3 bispecific molecules are expected to reduce or eliminate the inhibitory effects transduced by PD-1 and LAG-3 in T-cells thereby reinvigorating the T-cell population for enhanced anti-tumor cytotoxicity. Therefore, a skilled artisan would have reasonably expected that the immune checkpoint inhibition by Shah et al.’s PD-1 x LAG-3 bispecific molecules would be done twice over when compared to Rizvi et al.’s monospecific immune check point inhibitory molecule. This would have been especially obvious to a skilled artisan because the combination therapy taught by both Shah et al. and Rizvi et al. is intended to enhance the immune response against tumors via modulation of T-cell immunosuppression by the immune checkpoint inhibitory molecules.
As such, the applicant’s argument has not been found persuasive.
This is a New Ground of Rejection necessitated by applicant's amendment. Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable Shah et al. 2017 (WO2017019846, an IDS reference filed October 19, 2022) in view of Rizvi et al. 2016 (JCO 34(15_suppl), TPS3104, a reference of record) and Pereira et al. 2018 (MABS; 10(5), 693-711, a reference of record), as applied to claims 1 and 38, and further in view of Roth et al. 2007 (Cancer Res; 67 (16): 7893–7900, a reference of record).
Dependent claim 41 limits the B7-H3-expressing cancer to prostate cancer.
The combined teachings of Shah et al. in view of Rizvi et al. and Pereira et al. pertaining to claims 1 and 38 and the rationale for combining them is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the B7-H3-expressing cancer is prostate cancer.
Roth et al. teach that the T-cell coregulatory ligand B7-H3 is expressed by nearly every normal and pathologic prostate cell of epithelial origin (e.g. see page 7897, left column, first paragraph under “Discussion”). Where expression of B7-H3 is typically low within normal, atrophic, and hyperplastic prostate glands, levels of B7-H3 expression increase significantly within malignant prostate tumor cells. All prostate tumor specimens showed some degree of B7-H3 expression, as did four of the most commonly studied human prostate cancer cell lines. Moreover, 83% of these cancer specimens exhibited 100% tumor cell B7-H3 expression. Roth et al. show that B7-H3 is an independent prognostic marker for the assessment of prostate cancer patients. B7-H3 may be useful for the clinical evaluation of patients who have, or are to undergo, surgical treatment for their cancer, especially to identify high-risk patients who are at increased risk of cancer progression and, therefore, most likely to benefit from early and aggressive adjunctive therapy (e.g. see page 7897, left column, first paragraph under “Discussion”). Roth et al. further teach that B7-H3 is localized to the cytoplasmic membrane of prostate cancer cells, making B7-H3 a potential diagnostic and therapeutic target for treating prostate cancer (e.g. see page 7899, right column, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Shah et al. in view of Rizvi et al. and Pereira et al. as applied to claims 1 and 38, and to incorporate the teachings of Roth et al. to include that the B7-H3-expressing cancer is prostate cancer.
Given that levels of B7-H3 expression increase significantly within malignant prostate tumor cells and that B7-H3 is potential therapeutic target for treating prostate cancer (Roth et al.); it would have been obvious to a skilled artisan to experiment with applying the PD-1xLAG-3 bispecific binding molecule- afucosylated enoblituzumab combination therapy of Shah et al. in view of Rizvi et al. and Pereira et al. for treating a B7-H3-expressing cancer in the treatment of prostate cancer with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant's arguments filed January 23, 2026 have been fully considered but they are not persuasive.
The Applicant argues that Roth would not have overcome the deficiencies in the combination of Shah and Rizvi discussed above.
This is not found persuasive for the following reasons for the reasons stated above.
As such, the applicant’s argument has not been found persuasive.
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 7, 8, 19, 20, 22, 24, 29, 38, 39, and 43-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-30 of U.S. Application No. 19/239,433 (the ‘433 Application) in view of Shah et al. 2017 (WO2017019846, an IDS reference filed October 19, 2022), Rizvi et al. 2016 (JCO 34(15_suppl), TPS3104, a reference of record), and Pereira et al. 2018 (MABS; 10(5), 693-711, a reference of record).
The instant claims are drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
The claims in the ‘433 Application are drawn to method of treating cancer in a subject in need thereof, said method comprising administering to said subject an effective amount of a bi-specific Fc diabody capable of immunospecific binding to an epitope of PD-1 and to an epitope of LAG-3, wherein the anti-PD-1-LAG-3 bispecific Fc diabody comprises SEQ ID NOs: 16 and 17.
It is noted that the PD-1xLAG-3 bi-specific Fc diabody of the ‘433 Application is a species of the generic PD-1xLAG-3 binding molecule of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29, USPQ2d 2010 (Fed. Cir. 1993).
The claims in the ‘433 Application differ from the instant invention by not reciting that the cancer is a B7-H3-expressing cancer or that the PD-1xLAG-3 bi-specific Fc diabody is used in combination with an ADCC-enhanced Fc domain-comprising TA-binding molecule. The claims in the ‘433 Application also differ from the instant invention by not reciting that the ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose or that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab and is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks.
The teachings of Shah et al., Rizvi et al., and Pereira et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘433 Application to incorporate the teachings of Shah et al., Rizvi et al., and Pereira et al. to include that the PD-1xLAG-3 bi-specific Fc diabody is used in combination with an ADCC-enhanced Fc domain-comprising TA-binding molecule for treating a B7-H3-expressing cancer, wherein the ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose, and wherein the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab and is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks. This is because enoblituzumab, an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3, is expected to have additive or synergistic antitumor activity when combined with the immune checkpoint anti-PD-1 antibody, pembrolizumab in treating a B7-H3-expressing cancer (Rizvi et al.).
Given the desire to treat B7-H3-expressing cancers, the high expression of B7-H3 in many cancers, the expected synergistic effect of combining the anti-B7-H3 antibody enoblituzumab with an immune checkpoint inhibitory molecule for treating B7-H3-expressing cancer, that the Fc of enoblituzumab is optimized to enhance binding to the activating FcγR, and that glycoengineered therapeutic antibodies have been designed to eliminate core fucose on the Fc N-glycan to increase their binding affinity for FcγRIIIa and enhance their ADCC activity; it would be obvious to a skilled artisan to modify the method taught by the ‘433 Application and use the PD-1xLAG-3 bi-specific Fc diabody in combination with an ADCC-enhanced Fc domain-comprising TA-binding molecule for treating a B7-H3-expressing cancer, wherein the ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose, and wherein the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab with a reasonable expectation of success.
Enoblituzumab is Fc optimized to enhance binding to the activating FcγR (Rizvi et al.). It is well known that ADCC is a critical effector function triggered by a therapeutic antibody to eliminate target cells (Pereira et al.). ADCC is mediated by binding of the antibody Fc domain to an activating FcγR which is modulated by the N-linked glycosylation in the Fc region of the antibody (Pereira et al.). It is also well known that the absence of core fucose on the Fc N-glycan increases antibody binding affinity to activating FcγR leading to enhanced ADCC activity (Pereira et al.). Thus, it is desirable to design therapeutic antibodies with enhanced ADCC activity, such as those lacking core fucose, in order to improve their ability to eliminate target cells (Pereira et al.).
Given that enoblituzumab is expected to have a synergistic anti-tumor effect when combined with a monospecific immune check point inhibitory molecule, namely an anti-PD-1 antibody; a skilled artisan would reasonably expect that the combination of enoblituzumab with a bispecific immune check point inhibitory molecule, i.e. the ‘433 Application’s PD-1 x LAG-3 bispecific molecules, would at least have the same degree of synergy, if not more, as that described by Rizvi et al. for enhanced killing of B7-H3-expressing tumors. Like Shah et al.’s PD-1 x LAG-3 bispecific molecules, the ‘433 Application’s PD-1 x LAG-3 bispecific molecules are intended to coordinately bind to and inhibit two immune check point regulatory molecules. The PD-1 x LAG-3 bispecific molecules are expected to reduce or eliminate the inhibitory effects transduced by PD-1 and LAG-3 in T-cells thereby reinvigorating the T-cell population for enhanced anti-tumor cytotoxicity. Therefore, a skilled artisan would reasonably expect that the immune checkpoint inhibition by the ‘433 Application’s PD-1 x LAG-3 bispecific molecules would be done twice over when compared to Rizvi et al.’s monospecific immune check point inhibitory molecule. This would have been especially obvious to a skilled artisan because the combination therapy taught by both Shah et al. and Rizvi et al. is intended to enhance the immune response against tumors via modulation of T-cell immunosuppression by the immune checkpoint inhibitory molecules.
Furthermore, a skilled artisan would reasonably expect an afucosylated enoblituzumab to have enhanced ADCC function and, in turn, an enhanced ability to eliminate target cells especially when used in combination with a molecule that reinvigorates the T-cell population for enhanced anti-tumor cytotoxicity. Taken together, a skilled artisan would reasonably expect that the combination of afucosylated enoblituzumab with an immune checkpoint inhibitory PD-1xLAG-3 bispecific molecule would improve the method of treating cancer by combining a PD-1xLAG-3 bispecific molecule and a TA-binding molecule as taught by the ‘433 Application.
Regarding claims 8, 22, and 24 and further regarding claim 39, which recite that the PD-1 x LAG-3 bispecific molecule is administered as “a flat dose of from about 120 mg to about 800 mg,” “a flat dose of from about 300 mg or at a flat dose of about 600 mg,” “said flat dose is administered once about every 2 weeks or about once about every 3 weeks,” and “administering enoblituzumab at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks,” respectively; determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages, and like factors are well within the knowledge and expertise of the medical practitioner. It would have been obvious to one of ordinary skill in the art at the time the Applicant’s invention was filed, to determine all operable and optimal intervals of treatment because optimal intervals are an art-recognized, result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between the Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all of the various permutations of interval ranges as claimed in instant claims 8, 22, 24, and 39, it would be conventional and within the skill of the art to identify the optimal intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II A.
Regarding claims 43-45 which recite limitations drawn to the protein expression profile of the cancer cells prior to treatment, specifically the expression of LAG-3 (claim 43) and PD-1 (claim 44) in biopsied samples, and PD-L1 expression on the surface of the cancer cells (claim 45), these limitations do recite active steps of the instantly claimed method of treating cancer with a PD-1xLAG-3 bispecific molecule in a subject in need thereof. Thus, the PD-1xLAG-3 bispecific molecules taught by the ‘433 Application would necessarily bind to cells expressing the recited antigens and where these antigens are not expressed the claimed PD-1xLAG-3 bispecific molecules would not bind. Furthermore, as it is understood by the Examiner, given the content of the disclosure, the claimed PD-1xLAG-3 bispecific molecules are intended to antagonize PD-1 and LAG-3 expressed on T-cells, particularly those T-cells present in the tumor microenvironment (TME). The PD-1xLAG-3 bispecific molecules are intended to eliminate the inhibitory signals transduced by engagement of these immune check point regulators, thereby reinvigorating the anti-cancer activity of these T-cells. Thus, given that it is well-known that T-cells enter the TME, where they are known as tumor infiltrating lymphocytes (TILs), the TME of the tumors recited by the ‘433 Application would necessarily include TILs that express PD-1 and LAG-3 to which the PD-1xLAG-3 bispecific molecules could bind.
Therefore, the claims in the ‘433 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the claims have not in fact been patented.
This is a New Ground of Rejection necessitated by applicant's amendment. Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-30 of U.S. Application No. 19/239,433 (the ‘433 Application) in view of Shah et al. 2017 (WO2017019846, an IDS reference filed October 19, 2022), Rizvi et al. 2016 (JCO 34(15_suppl), TPS3104, a reference of record), and Pereira et al. 2018 (MABS; 10(5), 693-711, a reference of record), as applied to claims 1 and 38, and further in view of Roth et al. 2007 (Cancer Res; 67 (16): 7893–7900, a reference of record).
The instant claims are drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
The claims in the ‘433 Application are drawn to method of treating cancer in a subject in need thereof, said method comprising administering to said subject an effective amount of a bi-specific Fc diabody capable of immunospecific binding to an epitope of PD-1 and to an epitope of LAG-3, wherein the anti-PD-1-LAG-3 bispecific Fc diabody comprises SEQ ID NOs: 16 and 17.
It is noted that the PD-1xLAG-3 bi-specific Fc diabody of the ‘433 Application is a species of the generic PD-1xLAG-3 binding molecule of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29, USPQ2d 2010 (Fed. Cir. 1993).
The combined teachings of the ‘433 Application in view of Shah et al., Rizvi et al., and Pereira et al. pertaining to claims 1 and 38 and the rationale for combining them is outlined in the NSDP rejection above.
The combined reference teachings differ from the instant invention by not teaching that the B7-H3-expressing cancer is prostate cancer.
The teachings of Roth et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of the ‘433 Application in view of Shah et al., Rizvi et al., and Pereira et al. as applied to claims 1 and 38, and to incorporate the teachings of Roth et al. to include that the B7-H3-expressing cancer is prostate cancer.
Given that levels of B7-H3 expression increase significantly within malignant prostate tumor cells and that B7-H3 is potential therapeutic target for treating prostate cancer (Roth et al.); it would have been obvious to a skilled artisan to experiment with applying the PD-1xLAG-3 bispecific binding molecule-afucosylated enoblituzumab combination therapy of the ‘433 Application in view of Shah et al., Rizvi et al., and Pereira et al. for treating a B7-H3-expressing cancer in the treatment of prostate cancer with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the claims in the ‘433 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the claims have not in fact been patented.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 7, 8, 19, 20, 22, 24, 29, 38, 39, and 43-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims in the following U.S. Patents and co-pending Applications in view of Shah et al. 2017 (WO2017019846, an IDS reference filed October 19, 2022), Rizvi et al. 2016 (JCO 34(15_suppl), TPS3104, a reference of record), and Pereira et al. 2018 (MABS; 10(5), 693-711, a reference of record) for similar reasons as the claims in ‘433 Application above.
The instant claims are drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
Claims 1, 2, 12-18, 21-24, 35-38 and 49-62 of U.S. Patent No. 10,160,806 are drawn to the same or nearly the same bispecific Fc diabody that binds PD-1 and LAG-3 of the instant invention; and pharmaceutical compositions thereof.
Claim 29 of co-pending Application No. 18/515,530 is drawn to the same or nearly the same bispecific Fc diabody that binds PD-1 and LAG-3 of the instant invention, specifically PD-1xLAG-3 binding molecule that comprises, in its LAG-3-binding arm, the instantly claimed anti-LAG-3 VH and VL domain amino acid sequences.
Claims 28-50 of U.S. Patent No. 11,623,959 are drawn to species of PD-1xLAG-3 binding molecule, specifically a PD-1xLAG-3 binding molecule and a PD-1xLAG-3 binding bispecific diabody; and pharmaceutical compositions thereof.
Claims 6-20 of U.S. Patent Application No. 19/569,370 are drawn to a bispecific LAG-3 binding molecule. It is noted that the claims in the ‘370 Application were filed after (on 03/17/2026) the last Office Action that was mailed for the instant Application on 09/23/2025.
The PD-1xLAG-3 binding molecules in the above U.S. Patents and co-pending Applications are a species of the generic PD-1xLAG-3 binding molecule of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29, USPQ2d 2010 (Fed. Cir. 1993).
Regarding the claims in the above the U.S. Patents and co-pending Applications that fail to recite a method of treating a cancer in a subject in need thereof, it is noted that in Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003), the court applied nonstatutory double patenting to invalidate a claim without analyzing anticipation or obviousness. In this case, the earlier patent claimed a compound and the written description disclosed a single utility of that compound as administration to a human in amounts effective for inhibiting ß-lactamase. The later patent claimed nothing more than the earlier patent’s disclosed utility as a method of using the compound. Thus, the court found that the claims of the later patent and the claims of the earlier patent were not patentably distinct. The Geneva court relied on equitable principles, not an obviousness-type analysis, in reaching its conclusion. Id. at 1386, 68 USPQ2d at 1875 (quoting In re Byck, 48 F.2d 665, 666 (CCPA 1931)). See MPEP 804 II B.6.
This applies to the instant case where the claim limitation of “a method of treating a cancer…in a subject in need thereof” in instant claim 1 is a utility disclosed in the specification of the above U.S. Patents and co-pending Applications that fail to recite a method of treating a cancer in a subject in need thereof in the claims. Therefore, the instant application claims nothing more than the earlier patent’s disclosed utility as a method of using the compound. Thus, the instant claims and the claims of the U.S. Patents and co-pending Applications that fail to recite a method of treating a cancer in a subject in need thereof are not patentably distinct.
The claims in the above U.S. Patents and co-pending Applications differ from the instant invention by not reciting that the cancer is a B7-H3-expressing cancer or that the PD-1xLAG-3 bi-specific Fc diabody is used in combination with an ADCC-enhanced Fc domain-comprising TA-binding molecule. The claims in the ‘433 Application also differ from the instant invention by not reciting that the ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose or that the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab and is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks.
Regarding the ‘370 Application, the claims do not recite only a LAG-3 x PD-1 bispecific molecule.
The teachings of Shah et al., Rizvi et al., and Pereira et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the above U.S. Patents and co-pending Applications to incorporate the teachings of Shah et al., Rizvi et al., and Pereira et al. to include that the PD-1xLAG-3 bi-specific Fc diabody is used in combination with an ADCC-enhanced Fc domain-comprising TA-binding molecule for treating a B7-H3-expressing cancer, wherein the ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose, and wherein the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab and is administered at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks. This is because enoblituzumab, an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3, is expected to have additive or synergistic antitumor activity when combined with the immune checkpoint anti-PD-1 antibody, pembrolizumab in treating a B7-H3-expressing cancer (Rizvi et al.).
Given the desire to treat B7-H3-expressing cancers, the high expression of B7-H3 in many cancers, the expected synergistic effect of combining the anti-B7-H3 antibody enoblituzumab with an immune checkpoint inhibitory molecule for treating B7-H3-expressing cancer, that the Fc of enoblituzumab is optimized to enhance binding to the activating FcγR, and that glycoengineered therapeutic antibodies have been designed to eliminate core fucose on the Fc N-glycan to increase their binding affinity for FcγRIIIa and enhance their ADCC activity; it would be obvious to a skilled artisan to modify the method taught by the above U.S. Patents and co-pending Applications and use the PD-1xLAG-3 bi-specific Fc diabody in combination with an ADCC-enhanced Fc domain-comprising TA-binding molecule for treating a B7-H3-expressing cancer, wherein the ADCC- Enhanced Fc Domain comprises an engineered glycoform that is a complex N-glycoside-linked sugar chain that does not contain fucose, and wherein the TA-binding molecule is a B7-H3-binding molecule comprising the CDRs of enoblituzumab or that it is enoblituzumab with a reasonable expectation of success.
Enoblituzumab is Fc optimized to enhance binding to the activating FcγR (Rizvi et al.). It is well known that ADCC is a critical effector function triggered by a therapeutic antibody to eliminate target cells (Pereira et al.). ADCC is mediated by binding of the antibody Fc domain to an activating FcγR which is modulated by the N-linked glycosylation in the Fc region of the antibody (Pereira et al.). It is also well known that the absence of core fucose on the Fc N-glycan increases antibody binding affinity to activating FcγR leading to enhanced ADCC activity (Pereira et al.). Thus, it is desirable to design therapeutic antibodies with enhanced ADCC activity, such as those lacking core fucose, in order to improve their ability to eliminate target cells (Pereira et al.).
Given that enoblituzumab is expected to have a synergistic anti-tumor effect when combined with a monospecific immune check point inhibitory molecule, namely an anti-PD-1 antibody; a skilled artisan would reasonably expect that the combination of enoblituzumab with a bispecific immune check point inhibitory molecule, i.e. the above Patents’ and Applications’ PD-1 x LAG-3 bispecific molecules, would at least have the same degree of synergy, if not more, as that described by Rizvi et al. for enhanced killing of B7-H3-expressing tumors. Like Shah et al.’s PD-1 x LAG-3 bispecific molecules the above Patents’ and Applications’ PD-1 x LAG-3 bispecific molecules are intended to coordinately bind to and inhibit two immune check point regulatory molecules. The PD-1 x LAG-3 bispecific molecules are expected to reduce or eliminate the inhibitory effects transduced by PD-1 and LAG-3 in T-cells thereby reinvigorating the T-cell population for enhanced anti-tumor cytotoxicity. Therefore, a skilled artisan would reasonably expect that the immune checkpoint inhibition by the above Patents’ and Applications’ PD-1 x LAG-3 bispecific molecules would be done twice over when compared to Rizvi et al.’s monospecific immune check point inhibitory molecule. This would have been especially obvious to a skilled artisan because the combination therapy taught by both Shah et al. and Rizvi et al. is intended to enhance the immune response against tumors via modulation of T-cell immunosuppression by the immune checkpoint inhibitory molecules.
Furthermore, a skilled artisan would reasonably expect an afucosylated enoblituzumab to have enhanced ADCC function and, in turn, an enhanced ability to eliminate target cells especially when used in combination with a molecule that reinvigorates the T-cell population for enhanced anti-tumor cytotoxicity. Taken together, a skilled artisan would reasonably expect that the combination of afucosylated enoblituzumab with an immune checkpoint inhibitory PD-1xLAG-3 bispecific molecule would improve the method of treating cancer by combining a PD-1xLAG-3 bispecific molecule and a TA-binding molecule as taught by the ‘433 Application.
Regarding claims 8, 22, and 24 and further regarding claim 39, which recite that the PD-1 x LAG-3 bispecific molecule is administered as “a flat dose of from about 120 mg to about 800 mg,” “a flat dose of from about 300 mg or at a flat dose of about 600 mg,” “said flat dose is administered once about every 2 weeks or about once about every 3 weeks,” and “administering enoblituzumab at a dosage of about 6 mg/kg to about 18 mg/kg once about every 3 weeks,” respectively; determination of the optimal intervals of treatment and the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. The duration of treatment, the effective dosages, and like factors are well within the knowledge and expertise of the medical practitioner. It would have been obvious to one of ordinary skill in the art at the time the Applicant’s invention was filed, to determine all operable and optimal intervals of treatment because optimal intervals are an art-recognized, result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between the Applicant’s claimed method and that suggested by the teachings of the prior art, the differences would be appear minor in nature. Although the prior art do not teach all of the various permutations of interval ranges as claimed in instant claims 8, 22, 24, and 39, it would be conventional and within the skill of the art to identify the optimal intervals of treatment. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II A.
Regarding claims 43-45 which recite limitations drawn to the protein expression profile of the cancer cells prior to treatment, specifically the expression of LAG-3 (claim 43) and PD-1 (claim 44) in biopsied samples, and PD-L1 expression on the surface of the cancer cells (claim 45), these limitations do recite active steps of the instantly claimed method of treating cancer with a PD-1xLAG-3 bispecific molecule in a subject in need thereof. Thus, the PD-1xLAG-3 bispecific molecules taught by the above U.S. Patents and co-pending Applications would necessarily bind to cells expressing the recited antigens and where these antigens are not expressed the claimed PD-1xLAG-3 bispecific molecules would not bind. Furthermore, as it is understood by the Examiner, given the content of the disclosure, the claimed PD-1xLAG-3 bispecific molecules are intended to antagonize PD-1 and LAG-3 expressed on T-cells, particularly those T-cells present in the tumor microenvironment (TME). The PD-1xLAG-3 bispecific molecules are intended to eliminate the inhibitory signals transduced by engagement of these immune check point regulators, thereby reinvigorating the anti-cancer activity of these T-cells. Thus, given that it is well-known that T-cells enter the TME, where they are known as tumor infiltrating lymphocytes (TILs), the TME of the tumors recited by the above U.S. Patents and co-pending Applications would necessarily include TILs that express PD-1 and LAG-3 to which the PD-1xLAG-3 bispecific molecules could bind.
Therefore, the claims in the above U.S. Patents and co-pending Applications would render the instant claims obvious.
The NSDP rejections to co-pending Applications are provisional because the claims have not in fact been patented.
This is a New Ground of Rejection necessitated by applicant's amendment. Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims in the following U.S. Patents and co-pending Applications in view of Shah et al. 2017 (WO2017019846, an IDS reference filed October 19, 2022), Rizvi et al. 2016 (JCO 34(15_suppl), TPS3104, a reference of record), and Pereira et al. 2018 (MABS; 10(5), 693-711, a reference of record), as applied to claims 1 and 38, and further in view of Roth et al. 2007 (Cancer Res; 67 (16): 7893–7900, a reference of record) for similar reasons as the claims in ‘433 Application above.
The instant claims are drawn to a method of treating a cancer comprising administering a bispecific molecule that immunospecifically binds both PD-1 and LAG-3 (PD-1 x LAG-3 bispecific molecule) to a subject in need thereof, wherein said cancer is characterized by the expression of a Tumor Antigen (TA), wherein the method further comprises administering to said subject a Tumor Antigen (TA) Binding Molecule (TA-Binding Molecule), wherein the TA-Binding Molecule comprises an ADCC-Enhanced Fc Domain, and wherein said cancer is a B7-H3 expressing cancer.
Claims 1, 2, 12-18, 21-24, 35-38 and 49-62 of U.S. Patent No. 10,160,806 are drawn to the same or nearly the same bispecific Fc diabody that binds PD-1 and LAG-3 of the instant invention; and pharmaceutical compositions thereof.
Claim 29 of co-pending Application No. 18/515,530 is drawn to the same or nearly the same bispecific Fc diabody that binds PD-1 and LAG-3 of the instant invention, specifically PD-1xLAG-3 binding molecule that comprises, in its LAG-3-binding arm, the instantly claimed anti-LAG-3 VH and VL domain amino acid sequences.
Claims 28-50 of U.S. Patent No. 11,623,959 are drawn to species of PD-1xLAG-3 binding molecule, specifically a PD-1xLAG-3 binding molecule and a PD-1xLAG-3 binding bispecific diabody; and pharmaceutical compositions thereof.
Claims 6-20 of U.S. Patent Application No. 19/569,370 are drawn to a bispecific LAG-3 binding molecule. It is noted that the claims in the ‘370 Application were filed after (on 03/17/2026) the last Office Action that was mailed for the instant Application on 09/23/2025.
The PD-1xLAG-3 binding molecules in the above U.S. Patents and co-pending Applications are a species of the generic PD-1xLAG-3 binding molecule of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29, USPQ2d 2010 (Fed. Cir. 1993).
Regarding the claims in the above the U.S. Patents and co-pending Applications that fail to recite a method of treating a cancer in a subject in need thereof, it is noted that in Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003), the court applied nonstatutory double patenting to invalidate a claim without analyzing anticipation or obviousness. In this case, the earlier patent claimed a compound and the written description disclosed a single utility of that compound as administration to a human in amounts effective for inhibiting ß-lactamase. The later patent claimed nothing more than the earlier patent’s disclosed utility as a method of using the compound. Thus, the court found that the claims of the later patent and the claims of the earlier patent were not patentably distinct. The Geneva court relied on equitable principles, not an obviousness-type analysis, in reaching its conclusion. Id. at 1386, 68 USPQ2d at 1875 (quoting In re Byck, 48 F.2d 665, 666 (CCPA 1931)). See MPEP 804 II B.6.
This applies to the instant case where the claim limitation of “a method of treating a cancer…in a subject in need thereof” in instant claim 1 is a utility disclosed in the specification of the above U.S. Patents and co-pending Applications that fail to recite a method of treating a cancer in a subject in need thereof in the claims. Therefore, the instant application claims nothing more than the earlier patent’s disclosed utility as a method of using the compound. Thus, the instant claims and the claims of the U.S. Patents and co-pending Applications that fail to recite a method of treating a cancer in a subject in need thereof are not patentably distinct.
The combined teachings of the above U.S. Patents and co-pending Applications in view of Shah et al., Rizvi et al., and Pereira et al. pertaining to claims 1 and 38 and the rationale for combining them is outlined in the NSDP rejection above.
The combined reference teachings differ from the instant invention by not teaching that the B7-H3-expressing cancer is prostate cancer.
The teachings of Roth et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of the above U.S. Patents and co-pending Applications in view of Shah et al., Rizvi et al., and Pereira et al. as applied to claims 1 and 38, and to incorporate the teachings of Roth et al. to include that the B7-H3-expressing cancer is prostate cancer.
Given that levels of B7-H3 expression increase significantly within malignant prostate tumor cells and that B7-H3 is potential therapeutic target for treating prostate cancer (Roth et al.); it would have been obvious to a skilled artisan to experiment with applying the PD-1xLAG-3 bispecific binding molecule-afucosylated enoblituzumab combination therapy of the above U.S. Patents and co-pending Applications in view of Shah et al., Rizvi et al., and Pereira et al. for treating a B7-H3-expressing cancer in the treatment of prostate cancer with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the claims in the above U.S. Patents and co-pending Applications would render the instant claims obvious.
The NSDP rejections to co-pending Applications are provisional because the claims have not in fact been patented.
Applicant's arguments filed January 23, 2026 have been fully considered but they are not persuasive.
The Applicant argues that for at least the reasons discussed above, nothing in the claims of the above U.S. Patents and co-pending Applications suggest the currently claimed method combining dual checkpoint inhibition with an ADCC-enhanced TA-binding molecule in the treatment of a B7-H3 expressing cancer. The Applicant argues that, further, a POSA would not have had a reason to modify Shah to arrive at the claimed method. The Applicant argues that, thus, as discussed above, a POSA would not have used Shah to modify the claims of the above U.S. Patents and co-pending Applications as suggested by the Office.
The Applicant also argues that the combination of Shah and Pereira would not have led a POSA to a combination of dual PD-1/PD- L1 checkpoint inhibition and an ADCC-enhanced TA-binding molecule as currently claimed. The Applicant further argues that, thus, a POSA would not have used Shah and Pereira to modify the claims of the above U.S. Patents and co-pending Applications as suggested by the Office.
The Applicant also argues that the combination of Shah and Rizvi would not have led a POSA to a combination of dual PD-1/PD-L1 checkpoint inhibition and an ADCC-enhanced TA-binding molecule as currently claimed. The Applicant further argues that, thus, a POSA would not have used Shah and Rizvi to modify the claims of the above U.S. Patents and co-pending Applications as suggested by the Office.
The Applicant also argues that the combination of Shah, Rizvi and Roth would not have led a POSA to a combination of dual PD- 1/PD-L1 checkpoint inhibition and an ADCC-enhanced TA-binding molecule as currently claimed. The Applicant further argues that, thus, a POSA would not have used Shah, Rizvi and Roth to modify the claims of the above U.S. Patents and co-pending Applications as suggested by the Office.
It is noted that Applicant’s arguments with respect to Bang et al. 2017 (Ann. Oncol.; 28(4), 855-861, a reference of record) have been considered but are moot because the new grounds of rejection do not rely on the teachings of Bang et al. as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
This is not found persuasive for the following reasons for the reasons stated in the 103 rejection above.
As such, the applicant’s argument has not been found persuasive.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641