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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/31/2026 has been entered.
The claim listing filed March 31, 2026 is pending.
Claims 1-33, 35, 36 are canceled.
Claim 58 is new.
Claims 34 and 37-58 are pending.
Claims 47-49, 51, and 54-57 have been withdrawn under 37 CFR 1.142(b) as being drawn to a nonelected group.
Claims 34, 37-46, 50, 52, 53, and 58 are currently under consideration.
In view of the applicant’s amendment filed on March 31, 2026, the following objections and rejections are set forth.
Priority
The instant application is a 371 of PCT/CN2020/106309 filed 07/31/2020 and claims foreign priority to CN201911224135.5 filed 12/02/2019 and CN201910711122.4 filed 08/02/2019.
Certified translated copies of CN201911224135.5 and CN201910711122.4 have not been filed. Therefore, it is not clear if the foreign priority documents have adequate support for the instant claims.
Claim Objections
Claims 34, 37-46, 50, 52, 53, and 58 objected to because of the following informalities:
In claim 34, the term --the-- should be added before the term “anti-CTLA4” in line 11 and the term “the” should be deleted before the phrase “single chain antibody” in line 12.
In claims 37-46, 50, 52, 53, and 58, the term “an” should be deleted before the phrase “antigen-binding fragment thereof” in line 1 and/or 2.
Appropriate correction is required.
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.
Claims 40, 41, and 43 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 34 recites “comprises amino acid mutations consisting only of” in line 27. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 34 recites the broad recitation “comprises” and the claim also recites “consisting only of” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Amending claim to delete either “comprises” or “consisting only of” would obviate this part of the rejection.
Claims 40 and 41 recites “wherein the anti-PD1 or anti-CTLA4 immunoglobulin or the antigen-binding fragment thereof” in lines 2 and 3. However, claims 40 and 41 are dependent on claim 34 which recites that the anti-PD1 or anti-CTLA4 domains can be either an immunoglobulin of a single chain antibody, but not an antigen-binding fragment thereof. Therefore, the limitation “the antigen-binding fragment thereof” lacks antecedent basis and renders claims 40 and 41 indefinite.
Amending claims 40 and 41 to replace “the antigen-binding fragment thereof” with “the single chain antibody” would obviate this part of the rejection.
Claim 43 recites “wherein the linker fragment is (GGGGS)n” in line 2. However, claim 43 is dependent on claim 42 which recites three different linker fragments. Therefore, it is unclear which linker fragment claim 43 is referring to and the phrase “the linker fragment” lacks antecedent basis rendering the claim indefinite.
Amending claim 43 to recite “wherein the linker fragments are (GGGGS)n” in line 2 would obviate this part of the rejection.
Claim 58 recites “wherein the heavy chain constant region does not comprise any additional amino acid mutations” in line 2. Claim 58 is dependent on claim 34 which recites “wherein the heavy chain constant region comprises amino acid mutations consisting only of L234A, L235A, and G237A according to the EU numbering system” in lines 26 and 27. As noted above for claim 34, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 58 recites the broad recitation “comprises” and the claim also recites “consisting only of” and then “does not comprise” which are the narrower statements of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Canceling claim 58 would obviate this part of the rejection.
Written Description
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 that 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 that 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 37, 42-44, and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a bispecific antibody or an antigen-binding fragment thereof, comprising: a first protein functional region targeting PD-1, and a second protein functional region targeting CTLA4;wherein: the first protein functional region is an anti-PD1 immunoglobulin, and the second protein functional region is an anti-CTLA4 single chain antibody, or the first protein functional region is an anti-PD1 single chain antibody, and the second protein functional region is an anti- CTLA4 immunoglobulin
Dependent claim 37 limits the bispecific to that wherein the amino acid sequence of the VH of the anti-PD1 domain is selected from SEQ ID NO: 14 and SEQ ID NO: 18; and the amino acid sequence of the VL of the anti-PD 1 domain is selected from SEQ ID NO: 16 and SEQ ID NO: 20; and the amino acid sequence of the VH of the anti-CTLA4 domain is selected from SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 41 and SEQ ID NO: 43; and the amino acid sequence of the VL of the anti-CTLA4 domain is selected from SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 42 and SEQ ID NO: 44.
Dependent claim 42 limits the bispecific that wherein the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the VH of the anti-PD1 single chain antibody is linked to the VL of the anti-PD1 single chain antibody either directly or via a linker fragment; and/or the VH of the anti-CTLA4 single chain antibody is linked to the VL of the anti-CTLA4 single chain antibody either directly or via a linker fragment.
Dependent claim 43 limits the linker fragment to (GGGGS)n, n being a positive integer.
Dependent claim 44 limits the bispecific to that wherein the number of each of the first protein functional region and second protein functional region is independently 1, 2 or more.
Dependent claim 46 limits the limits the bispecific to that wherein: the first protein functional region is linked to the second protein functional region via a first linker fragment; the anti-CTLA4 single chain antibody is linked to the C terminus of the heavy chain of the anti-PD1 immunoglobulin; the VH of the anti-CTLA4 single chain antibody is linked to the VL of the anti- CTLA4 single chain antibody via a second linker fragment; and wherein the first linker fragment and the second linker fragment are the same or different.
Regarding claim 37, which is drawn to an anti-PD-1/CTLA4 bispecific antibody with any combination of the recited VH and VL domain amino acid sequences for the respective binding domains, the Applicant has disclosed the anti-PD-1 antibody 14C12 and its humanized version 14C12H1L1 (e.g. see page 33). It is noted that the murine 14C12 antibody comprises a VH and VL as SEQ ID NOs: 14 and 16 and the humanized 14C12H1L1 antibody comprises a VH and VL as SEQ ID NOs: 18 and 20 (e.g. see pages 33 and 34).
The Applicant has also disclosed the anti-CTLA4 antibody 4G10 and its humanized versions 4G10H1L1, 4G10H3L3, 4G10H1V, and 4G10H3V (e.g. see pages 20 and 21). It is noted that the murine 4G10 antibody comprises a VH and VL as SEQ ID NOs: 2 and 4, the humanized 4G10H1L1 antibody comprises a VH and VL as SEQ ID NOs: 6 and 8, the humanized 4G10H3L3 antibody comprises a VH and VL as SEQ ID NOs: 10 and 12, the humanized 4G10H1V antibody comprises a VH and VL as SEQ ID NOs: 41 and 42, and the humanized 4G10H3V antibody comprises a VH and VL as SEQ ID NOs: 43 and 44 (e.g. see pages 20, 21, and 37).
Regarding the claims which are drawn to any type of linker fragment (claims 42, 43, and 46), the Applicant has disclosed bispecific antibodies (BiAb001-004) that comprise Linker 1 ((GGGGS)3 (SEQ ID NO: 25)) or Linker 2 ((GGGGS)4 (SEQ ID NO: 26)) connecting the first and second protein functional regions and Linker 2 ((GGGGS)4 (SEQ ID NO: 26)) connecting the VH and VL of the single chain antibody (e.g. see Table A on page 36).
Regarding claim 44, which is drawn to the bispecific comprising any number of first and second protein functional regions, the Applicant has only disclosed bispecific antibodies with one first protein functional region and one second protein functional region (e.g. see Table A on page 36).
When given the broadest reasonable interpretation in light of specification, the bispecific antibodies may comprise (I) any combination of the recited VH and VL domain amino acid sequences for the respective binding domains, including the paring of murine and humanized domains (claim 37), (II) any linker fragment connecting the first and second protein functional regions and any linker fragment connecting the VH and VL of the single chain antibody (claims 42, 43, and 46), and (III) any number of first and second protein functional regions (claim 44).
It is noted that claim 38 recites proper combinations for the VH and VL domain amino acid sequences for the respective binding domains.
It is further noted that none of the claims recite sufficient structure for the genera of bispecific antibodies that comprise any linker fragment connecting the first and second protein functional regions and any linker fragment connecting the VH and VL of the single chain antibody or any number of first and second protein functional regions.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Regarding the claim that is drawn to an anti-PD-1/CTLA4 bispecific antibody with any combination of the recited VH and VL domain amino acid sequences for the respective binding domains (claim 37), Bujotzek et al. 2016 (MABS. 8 (2), 288-305) teach that exchanging the framework regions of an antibody in the process of humanization has a potential effect on how the CDRs are presented to the antigen, and thus on the antigen-binding properties (e.g. see page 289, paragraph spanning left and right columns). To increase the probability of obtaining a satisfactory humanized version of the original antibody, it is common practice to generate multiple humanization variants of the heavy chain and light chain variable regions (VH and VL), differing, e.g., in the choice of acceptor framework, or the number and location of forward and backward mutations (e.g. see page 289, paragraph spanning left and right columns).
Bujotzek et al. also teach that there is a notable variability in the parameters of VH-VL orientation and it seems likely that modulating VH-VL orientation not only is a necessary means to accommodate the diverse antigenic shapes that antibodies are confronted with, but also a mechanism to further diversify the composition (and thus increase the possible number) of antibody paratopes - in addition to the well-known mechanisms of diversification involving variations in length and sequence of the CDRs (e.g. see page 289, right column, second paragraph). It is reasonable to assume that changes in VH-VL orientation (e.g., caused by exchanging the β-sheet framework during humanization) might induce changes with regard to antigen binding (e.g. see page 289, right column, second paragraph).
Thus, in view of art, skilled artisans would reasonably understand that it is unpredictable to pair any VH and any VL domain and expect proper VH-VL orientation and retention of antigen-binding.
This applies to instant claim 37 which is drawn to an anti-PD-1/CTLA4 bispecific antibody with any combination of the recited VH and VL domain amino acid sequences for the respective binding domains. Claim 37 encompasses VH and VL combinations that include one murine and one humanized domain and VH and VL domains from different humanization strategies.
Regarding the claims which are drawn to any type of linker fragment connecting the first and second protein functional regions (claims 42, 43, and 46), Madsen et al. 2024 (Front. Bioeng. Biotechnol. 12:1352014, 1-13) teach that glycine-serine linkers of 10–25 amino acids are commonly used for fusion of exogenous antigen-binding domains as these exhibit favorable flexibility and stability in aqueous solutions (e.g. see page 5, right column, second paragraph). Other bsAb constructs have utilized linkers derived from natural antibody linker regions such as the antibody hinge region or the flexible link connecting Fv and CH1/Cκ. The choice of an appropriate linker is important to ensure proper spacing and display of the antigen-binding domains. One study found linker lengths to affect both antigen-binding and stability of DVD-Ig molecules (e.g. see page 5, right column, second paragraph).
Thus, the art teaches that selecting a proper linker for connecting the first and second protein functional regions of an antibody is unpredictable and does not guarantee antigen binding.
Regarding the claims which are drawn to any type of linker fragment connecting the VH and VL of the scFv (claims 42, 43, and 46), Kussia and Tessema 2024 (J Immunol Res. 2024, 1804038, 1-24) teach that the length and sequence of the linker peptide plays a significant role in determining the binding feature, specificity, folding, and solubility of scFv antibodies (e.g. see paragraph spanning pages 2 and 3). The linkers are mostly within 15–20 amino acid sequences and rich in glycine and serine residues, nevertheless, it can be optimized up to 35 amino acids. The glycine–serine-rich linker sequences are the most commonly used due to their flexible nature. In vitro studies, however, show that those repeated sequences carry problems in PCR-based experiments, appear immunogenic, and display less stability than nonrepetitive linkers. Moreover, serine, particularly and other charged residues such as glutamic acid and lysine (as EAAAK)2, if included in linker sequences, have improved the rigidity and solubility of a scFv (e.g. see paragraph spanning pages 2 and 3).
Thus, the art teaches that selecting a proper linker for connecting the VH and VL of the scFv is unpredictable and does not guarantee antigen binding.
Regarding the claim that is drawn to the bispecific comprising any number of first and second protein functional regions (claim 44), Deyev and Lebedenko 2008 (BioEssays 30:904–918) teach that increased multivalency does not always cause the increase in antigen binding (e.g. see page 914, left column, first paragraph). The precise increase in affinity gained through avidity depends on many factors, including steric effects, local concentration and accessibility of adjacent epitopes, and the conformational flexibility of both target antigens and binding molecules of the multimer. For example, it has been shown that tetramer 4D5–p53 has no higher avidity than the dimer, presumably, because the simultaneous binding to more than two antigen molecules on the surface of cells is not possible due to steric hindrance (e.g. see page 914, left column, first paragraph).
Deyev and Lebedenko also teach that the incorporation of long enough hinge peptide linkers for binding antibody moieties would allow for the avoidance the steric hindrances (e.g. see page 914, left column, second paragraph). Deyev and Lebedenko also teach increasing the diameter and peripheral positions of the N and C termini of a multimeric binding protein may allow for optimal presentation of antibody fragments thanks to their flexibility and ensure the best interaction of multimeric antibody with multiple natural antigens (e.g. see page 914, left column, third paragraph).
Ultimately, Deyev and Lebedenko teach that the translation of the theoretical advantages of multivalent constructs into real multiple binding is affected by several factors, above all, by steric interference (e.g. see page 914, paragraph spanning left and right columns). Moving from the designs of constructs to actual applications, the situation of multivalent recombinant antibodies, is not straightforward. It requires detailed consideration of a three-dimensional structure, flexibility and geometry of interacting partners, namely, multi-valent antibody constructs and their targets.
Thus, the art teaches that engineering a bispecific comprising any number of first and second protein functional regions is unpredictable and does not guarantee antigen binding. Optimizing for flexibility and geometry, such as through linkers, protein diameter, and the peripheral positions of the N and C termini, are important considerations in the design of the multimeric bispecific binding antibodies.
As noted above, the Applicant has disclosed (I) murine and humanized anti-PD-1 and anti-CTLA4 antibodies with precise VH and VL combination, (II) four bispecific anti-PD-1/anti-CTLA4 antibodies with specific linkers between the anti-PD-1 and anti-CTLA4 binding regions and between the VH and VL of the scFv, (II) and only bispecific antibodies with one first protein functional region and one second protein functional region.
Such a disclosure does not serve to provide sufficient written description of the claimed to genera of bispecific antibodies that comprise (I) any combination of the recited VH and VL domain amino acid sequences for the respective binding domains, including the paring of murine and humanized domains (claim 37), (II) any linker fragment connecting the first and second protein functional regions and any linker fragment connecting the VH and VL of the single chain antibody (claims 42, 43, and 46), and (III) any number of first and second protein functional regions (claim 44).
The disclosure does not identify sufficient structural features or combination of features which give rise to the function of PD-1 and CTLA4 binding. Additionally, there does not appear to be any reasonable shared structure present in the genera of bispecific antibodies which gives rise to their functional activity. Ultimately, identifying a bispecific antibody on the basis of binding to PD-1 and CTLA4 rather than by identifying the sequence/structure, namely specific combinations of VH and VL domains, specific linker fragments, and number of first and second protein functional regions, of the bispecific antibody in question is generally insufficient to provide written description.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of bispecific anti-PD-1/anti-CTLA4 antibodies as encompassed by the claims at the time the instant application was filed.
Amending the claims to: (I) cancel claim 37, given that claim 38 already recites the correct VH and VL pairs; (II) limit the linker fragments in claims 42, 43, and 46 to Linker 1 ((GGGGS)3 (SEQ ID NO: 25)) or Linker 2 ((GGGGS)4 (SEQ ID NO: 26)) connecting the first and second protein functional regions and Linker 2 ((GGGGS)4 (SEQ ID NO: 26)) connecting the VH and VL of the single chain antibody; and (III) limit the number of first and second protein functional regions to no more than two in claim 44 would obviate this part of the rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 34, 37-46, 50, 52, 53, and 58 stand rejected under 35 U.S.C. 103 as being unpatentable over Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) in view of McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025).
Independent claim 34 is drawn to a bispecific antibody or an antigen-binding fragment thereof, comprising: a first protein functional region targeting PD-1, and a second protein functional region targeting CTLA4;
wherein: the first protein functional region is an anti-PD1 immunoglobulin, and the second protein functional region is an anti-CTLA4 single chain antibody, or the first protein functional region is an anti-PD1 single chain antibody, and the second protein functional region is an anti-CTLA4 immunoglobulin;
wherein: the functional region targeting PD-1 comprises a heavy chain variable region (VH) comprising HCDR1-HCDR3 of amino acid sequences set forth in SEQ ID NOs: 27-29, respectively, and a light chain variable region (VL) comprising LCDR1-LCDR3 of amino acid sequences set forth in SEQ ID NO: 30, RAN, and SEQ ID NO: 32, respectively; and functional region targeting CTLA4 comprises a VH comprising HCDR1-HCDR3 of amino acid sequences set forth in SEQ ID NOs: 33-35, respectively, and a VL comprising LCDR1-LCDR3 of amino acid sequences set forth in SEQ ID NO: 36, GTN, and SEQ ID NO: 38, respectively;
wherein the anti-PD1 immunoglobulin or anti-CTLA4 immunoglobulin is a human IgG1 subtype; and wherein the anti-PD1 immunoglobulin or anti-CTLA4 immunoglobulin further comprises a heavy chain constant region and wherein the heavy chain constant region comprises amino acid mutations consisting only of L234A, L235A, and G237A according to the EU numbering system.
Regarding claim 34, Li et al. teach a bifunctional antibody comprising a first functional area that targets PD-1 and a second function area that targets CTLA4 (e.g. see claim 1). The first and second functional areas are independently an immunoglobulin or an antigen-binding fragment, for example, a single-chain antibody (e.g. see claim 1). Li et al. also disclose that the immunoglobulin is IgG1 and the bifunctional antibody has the same CDRs as recited in instant claim 1 (e.g. see antibodies 4G10 and 14C12 and claims 5 and 7).
Regarding claims 37 and 38, Li et al. also teach the instantly claimed anti-CTLA4 VH amino acid sequences of SEQ ID NOs: 2, 6, 10, and 14; anti-CTLA4 VL amino acid sequences of SEQ ID NOs: 4, 8, and 12; claimed anti-PD-1 VH amino acid sequences of SEQ ID NOs: 16 and 20; anti-CTLA4 VL amino acid sequences of SEQ ID NOs: 18 and 22. See sequences alignments for VH and VL in the Office Action mailed on July 11, 2025.
Regarding claims 39 and 46, Li et al. also teach the heavy chain constant region Ig gamma-1chain C, ACCESSION: P01857, and the light chain constant region Ig kappa chain C region, ACCESSION: P01834 (e.g. see page 26).
Regarding claims 42 and 43, Li et al. also teach that the first protein function area and the second protein function area are directly connected to or are connected by a junction fragment; preferably, the junction fragment is (GGGGS)n, where n is a positive integer, such as 1, 2, 3, 4, 5 or 6 (e.g. see claim 2).
Regarding claim 44, Li et al. also teach that the first protein functional area and the second protein functional area are independently 1, 2, or more (e.g. see claim 4).
Regarding claim 45, Li et al. also teach that the single-chain antibody is connected to the C-terminal of the heavy chain of immunoglobulin (e.g. see claim 6).
Regarding claims 50 and 52, Li et al. further teach a conjugate that includes the bispecific antibody and coupling moiety, wherein the coupling moiety is a detectable marker; specifically a radioisotope, fluorescent material, luminescent substance, coloring matter or enzyme (e.g. see claim 16); and a pharmaceutical composition that includes the bispecific antibody and pharmaceutically acceptable carrier and/or excipient (e.g. see claim 19).
Regarding claim 53, Li et al. also teach that their bispecific antibodies, BiAb003, BiAb004 and 14C12H1L1, were combined with the T cell antibodies 4G10H3L3, Nilolumab, and Ipilimumab, which are considered to be anti-tumor chemotherapeutics (e.g. see page 34, example 3.3). This antibody combination was applied to CD4+ PBMCs in the presence of buffer (e.g. see page 34, example 3.3).
The reference teachings differ from the instant invention by not teaching that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting only of L234A, L235A, and G237A according to the EU numbering system.
McCarthy et al. teach antibody and other Fc-containing molecules with variations in the Fc region with reduced binding to Fc gamma receptors and resulting activity that can be used in the treatment of various diseases and disorders (e.g. see Abstract). McCarthy et al. also teach recombinant polypeptides comprising (a) a binding domain capable of binding a target molecule; and (b) an Fc domain comprising a mutated IgG1 constant domain comprising mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis or cell mediated destruction of the target (e.g. see [0011]). Specifically, the mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S in IgG1 reduce binding to FcγRI, FcγRII, and FcγRIII, and reduce ADCC and CDC activities (e.g. see [0050]). CDC refers to the form of cytotoxicity in which the complement cascade is activated by the complement component C1q binding to antibody Fc (e.g. see [0034]).
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 Li et al. to incorporate the teachings of McCarthy et al. to include that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A. Given the well-known and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would have been obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to have modified Li et al.’s anti-PD-1/CTLA-4 bispecific antibody to further comprise the L234A, L235A, and G237A mutations described by McCarthy et al. in the Fc domain with a reasonable expectation of success.
It is noted that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03. This applies to the instant case where claim 34 recites that the heavy chain constant region “comprises amino acid mutations consisting only of L234A, L235A, and G237A.” Therefore, given the broadest reasonable interpretation, the heavy chain may comprise additional mutations to the L234A, L235A, and G237A, such as those recited in McCarthy et al. (i.e. P238A, H268A, A330S and P331S).
Regarding claims 40 and 41, the properties recited in these claims flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
Therefore, the bispecific antibody taught by Li et al. in view of McCarthy et al. would necessarily have the properties recited in claims 40 and 41, especially in the absence of evidence to the contrary.
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.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that claim 34 has been amended to recite "wherein the heavy chain constant region comprises amino acid mutations consisting only of L234A, L235A, and G237A according to the EU numbering system” and that the amino acid sequence of the heavy chain constant domain includes only the three recited amino acid mutations. Furthermore, the Applicant argues that new claim 58 has been added to additionally specify that the heavy chain constant region does not comprise any additional amino acid mutations.
The Applicant further argues that this specific set of heavy chain constant region amino acid mutations is not recited in McCarthy, which instead requires the presence of four additional mutations (P238A, H268A, A330S, and P331S). The Applicant asserts that there is nothing in McCarthy that suggests picking and choosing the amino acid mutations recited in the present claims from the group recited by McCarthy.
The Applicant also argues that, furthermore, Applicant's prior arguments made in the context of the obviousness rejection under Lo et al. apply equally to McCarthy - the effect of Fc mutations in the context of antibodies is unpredictable. The Applicant asserts that as described in the response filed October 10, 2025, the present application shows that the same Fc mutations result in disparate effect on the Fc region of antibodies having different variable domains. The Applicant further asserts that in Example 7 and Table 7 of the present application illustrating the different effect of the L234A, L235A, and G237A mutations in the context of a control anti-PD- L1 antibody (5C10H2L2-IgGlmt) and an exemplary embodiment of the presently claimed antibody (BiAb004(hG1TM)). The Applicant argues that, therefore, even if McCarthy did describe this specific set of only three mutations, which Applicant asserts McCarty does not, the effects of these three mutations in the context of a different antibody are unpredictable.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s argument that the heavy chain constant domain includes only the three recited amino acid mutations and additional amino acid mutations; note that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03.
This applies to the instant case where claim 34 recites that the heavy chain constant region “comprises amino acid mutations consisting only of L234A, L235A, and G237A.” Therefore, given the broadest reasonable interpretation, the heavy chain may comprise additional mutations to the L234A, L235A, and G237A, such as those recited in McCarthy et al. (i.e. P238A, H268A, A330S and P331S).
The Applicant is invited to amend claim 34 to recite “wherein the heavy chain constant region consists of L234A, L235A, and G237A amino acid mutations according to the EU numbering system” in order to limit the claims to only these three mutations.
Regarding the Applicant’s arguments that the effect of Fc mutations in the context of antibodies is unpredictable and that the same Fc mutations result in disparate effect on the Fc region of antibodies having different variable domains; note that McCarthy et al. clearly teach that the L234A, L235A, G237A, P238A, H268A, A330S and P331S mutations in IgG1 antibodies, in general, reduce binding to FcγRI, FcγRII, and FcγRIII, and reduce ADCC and CDC activities. It is noted that CDC is a form of cytotoxicity in which the complement cascade is activated by C1q binding to antibody Fc (McCarthy et al.). Thus, the reduced CDC activity by McCarthy et al.’s IgG1 Fc mutants would presumably be the result of inhibiting C1q binding to Fc. Fc region mutations are generally known to be transferable to any antibody with a reasonable expectation of success.
Furthermore, while the Applicant asserts that the effect of Fc mutations comprising L234A, L235A, and G237A depends heavily on the context of the rest of the antibody (e.g., the variable domains); Li et al. disclose an antibody comprising a variable domain that is identical to instant BiAb004(hGITM). Thus, the anti-PD-1/CTLA-4 bispecific antibody comprising the L234A, L235A, and G237A mutations taught by Li et al. in view of McCarthy et al. would have the same structure as the BiAb004(hGITM) disclosed in the specification and would necessarily have the same function of no measurable binding to complement Clq as asserted by the Applicant, especially in the absence of evidence to the contrary.
Thus, McCarthy et al. provides the motivation for a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to combine Li et al.’s teachings with McCarthy et al.’s and experiment with modifying Li et al.’s anti-PD-1/CTLA-4 bispecific antibody to further comprise the L234A, L235A, and G237A mutations described by McCarthy et al. in the Fc domain with a reasonable expectation of success.
As such, the applicant’s arguments have not been found persuasive.
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.
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.
Anticipation-type
Claim 52 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18/264,191 (the ‘191 Application) for the reasons of record.
Claim 52 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/291,128 (the ‘128 Application) for the reasons of record.
Claims 34, 40-44, and 58 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/286,755 (the ‘755 Application) for the reasons of record.
Claim 52 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-18 and 20-22 of copending Application No. 18/840,378 (the ‘378 Application) for the reasons of record.
Obviousness-type
Claims 34, 37-46, and 58 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/291,128 (the ‘128 Application) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) for the reasons of record.
Claims 34, 37-46, and 58 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 9-18 and 20-22 of copending Application No. 18/840,378 (the ‘378 Application) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) for the reasons of record.
Claims 34, 37, 38, 40-45, and 58 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 36 of co-pending Application 17/996,878 (the ‘878 Application) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) for the reasons of record.
Claims 34-38, 40-45, 50, 52, 53, and 58 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the following co-pending applications in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) for similar reasons as discussed in the obviousness-type nonstatutory double patenting rejection to the ‘878 Application above for the reasons of record.
Claims 14, 18, 19, 21, 27, 29, 30, 35, and 37 of copending Application 17/779,425.
Claims 1, 2, and 20 of copending Application 18/024,478.
Claims 32, 33, 35-39, and 43-47 of copending Application 17/630,477.
Claims 23, 26, and 28 of copending Application 18/696,546.
Claims 9, 15-29, and 35-46 of copending Application 18/264,138.
Claims 34, 37, 38, 40-45, 50, 52, 53, and 58 stand rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-12, 17, 20, and 22-28 of U.S. Patent No. 11,578,128 (the ‘128 Patent, a reference of record) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for the reasons of record.
Claims 34, 37, 38, 40-45, 50, 52, 53, and 58 (and claims 39 and 46 in the case of the ‘755, ‘128, and ‘722 Applications) stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the following co-pending applications in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for similar reasons as discussed in the obviousness-type nonstatutory double patenting rejection to the ‘128 Patent for the reasons of record.
Claims 26-30 of co-pending Application No. 18/024,471.
Claims 1 and 3-20 of co-pending Application No. 18/264,191.
Claims 1-8, 10-12, 14, 15, and 17 of co-pending Application 18/286,755.
Claims 1, 2, 4, 5, and 7-11 of copending Application No. 18/291,128.
Claim 11 of copending Application 18/250,010.
Claims 9-18 and 20-22 of Application No. 18/840,378.
Claims 1-19 and 22 of copending Application No. 19/162,722.
Claims 27-33 of copending Application No. 19/365,106.
Claims 31-48 of copending Application No. 19/473,423.
Claims 34, 37, 38, 40-45, 50, 52, 53, and 58 stand rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,479,608 (the ‘608 Patent, a reference of record) in view of in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for the reasons of record.
Claims 34, 37, 38, 40-45, 50, 52, 53, and 58 stand rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 2, and 6 of U.S. Patent No. 12,076,398 (the ‘398 Patent, a reference of record) in view of in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for the reasons of record.
Claims 34, 37, 38, 40-45, 50, 52, 53, and 58 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the following co-pending applications in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached, a reference of record) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for similar reasons as discussed in the obviousness-type nonstatutory double patenting rejection to the ‘398 Patent for the reasons of record.
Claims 29-48 of copending Application 19/176,458.
Claims 1-7, 9, 10, 14-16, 22, and 32-39 of copending Application 17/996,878.
Claims 16 and 19 of copending Application 18/696,546.
Claims 9, 15-29, and 35-46 of copending Application 18/264,138.
Claims 24, 35-39, 40, 43-55, and 58 of copending Application 17/272,121.
The Applicant’s arguments have been fully considered but have not been found persuasive.
In the remarks filed 03/31/2026, the Applicant summarized the NSDP rejections from the Office Action mailed on 11/03/2025. See copy of Table 1 below.
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805
634
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438
633
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The Applicant argues that each of Rejections 1-17 in Table 1 relies on a reference application that has an effective filing date after the effective filing date of the present application. The Applicant asserts that none of these references (Application Nos. 18/264,191; 18/291,128; 18/286,755; 18/840,378; 18/024,471; 18/250,010; 19/473,423; 18/264,138; 19/162,722; and 17/996,878) are proper references for non-statutory ODP rejections.
The Applicant also argues that for rejections 14, 16, 17, and 22 in Table 1 that the Office improperly relies on secondary references to formulate the ODP rejections. The Applicant asserts that ODP rejections require (1) a comparison of the claims and (2) use of secondary references, including the specifications of the reference application, only to construe a reference claim and (3) an articulated reasoning based solely on the content of the claims as to why one of skill in the art would conclude that the claims of the present application would have been an obvious variant of the reference claims. The Applicant argues that Rejections 14, 16, 17, and 22 each fail on at least one of these requirements.
The Applicant argues that the claims of the present application are directed to an anti-CTLA4/anti-PD1 bispecific antibody. The Applicant asserts that for the reasons discussed below, the Office improperly relies on Li as a secondary reference for each of rejections 14 (Reference Application No. 18/264,138 - the "'138 Application"), 16 & 17 (Reference Application No. 17/996,878 - the "'878 Application") and 22 (Reference Application No. 17/272,121 - the "'121 Application"). The Applicant argues that for each of these rejections, the Examiner does not use Li to construe the claims, but rather to draw out disclosure of claim elements present in the currently pending claims in order to formulate the ODP rejections, which is not permitted.
Further regarding the NSDP rejection #14, the Applicant argues that the claims of the '138 Application are directed to combinations of anti-TIGIT antibodies and anti-VEGF/anti-PD1 bispecific antibodies. The Applicant asserts that although the '138 Application claims teach an anti-PD 1 antibody, they do not teach an anti-CTLA4 binding domain as recited in present claim 34. The Applicant argues that instead, the examiner relies on the disclosure of the secondary reference of Li and its discussion of CTLA4 binding domains, which is not permitted.
The Applicant asserts that as explained above, the Examiner does not use the disclosure of Li to construe the claims of the '138 Application because, as discussed above, the claims of the '138 Application do not teach or suggest an anti-CTLA4 binding domain. The Applicant argues that, therefore, it is improper for the Examiner to use Li as prior art and draw out disclosure relating to anti-CTLA4 antibodies to formulate the instant double patenting rejection.
The Applicant argues that furthermore, the Examiner does not provide articulated reasoning based solely on the content of the claims of the '138 application as to why it would be obvious, for example, to replace an anti-VEGF binding domain with an anti-CTLA4 binding domain. The Applicant asserts that an anti-VEGF binding domain targets VEGF while an anti-CTLA4 binding domain targets CTLA4. The Applicant assert that these are completely different binding domains with unique CDRs targeting completely different antigens. The Applicant argues that based on these structural and functional differences alone, a person of skill in the art would not be motivated upon their review of the '138 claims to substitute the anti-VEGF binding domain with the anti- CTLA4 binding domain of the instant claims.
Further regarding Rejections 16, 17, and 22, the Applicant’s arguments are substantially the same as those made for rejection 14 immediately above.
Regarding rejections 17, 18, 19, 20, 21, and 22, the Applicant argues that the present claims are patentably distinct from the claims of the reference patents and applications. The Applicant asserts that as noted above, Applicant has amended claim 34 to recite, in pertinent part, that the heavy chain of the antibody comprises the heavy chain constant region mutations consisting only of L234A, L235A, and G237A according to the EU numbering system. The Applicant asserts that as acknowledged by the Examiner, Li does not teach these mutations. The Applicant asserts that as argued above, McCarthy does not teach or suggest this specific set of mutations. The Applicant argues that for at least these reasons, the present claims are patentability distinct from the reference patents and applications used in rejections 17, 18, 19, 20, 21, 22 (17/996,878; US 11,578,128; 19/365,106; 11,479,608; 12,076,398; and 17/272,121).
Regarding rejection 23, the Applicant argues that the reference application is not published and information about the currently pending claims is not publicly available. The Applicant asserts that this application is a pending continuation of US 12,390,458, which is directed to combinations of a PD 1 antibody and quinoline derivatives. Applicant requests that the Examiner reconsider the present rejection over the '458 Application in view of the arguments provided above regarding appropriate use of secondary references and the non-obviousness of the present claims over the cited art in the event that they are applicable to the unpublished claims of the '458 Application. Alternatively, Applicant requests that the rejection be held in abeyance until the '458 Application publishes and Applicant is able to evaluate the claimed subject matter.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that none of the references (Application Nos. 18/264,191; 18/291,128; 18/286,755; 18/840,378; 18/024,471; 18/250,010; 19/473,423; 18/264,138; 19/162,722; and 17/996,878) for each of Rejections 1-17 are proper references for non-statutory ODP rejections because they rely on a reference application that has an effective filing date after the effective filing date of the present application; note that it is proper for an examiner to make a provisional double patenting rejection between co-pending Applications regardless if the instant Application has an earlier filing date. See MPEP 804I.B.
An examiner may become aware of two or more copending applications which share the same inventive entity, at least one common (joint) inventor, a common applicant, and/or a common owner/assignee, or that claim an invention resulting from activities undertaken within the scope of a joint research agreement as defined in 35 U.S.C. 102(c) or pre-AIA 35 U.S.C. 103(c)(2) and (3), that would raise an issue of double patenting if one of the applications became a patent. Where this issue can be addressed without violating the confidential status of applications (35 U.S.C. 122 ), the courts have sanctioned the practice of making applicant aware of the potential double patenting problem if one of the applications became a patent by permitting the examiner to make a provisional rejection on the ground of double patenting. A provisional double patenting rejection should be made and maintained by the examiner until the rejection has been obviated or is no longer applicable except as noted below. MPEP 804I.B.
If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent. MPEP 804I.B.1(b)(i)
In the instant case, the provisional nonstatutory double patenting rejections against Application Nos. 18/264,191; 18/291,128; 18/286,755; 18/840,378; 18/024,471; 18/250,010; 19/473,423; 18/264,138; 19/162,722; and 17/996,878 will not be withdrawn at this time in view of the remaining non-double patenting rejections outlined above. While the Examiner agrees that that instant Application has an early effective filing date than Application Nos. 18/264,191; 18/291,128; 18/286,755; 18/840,378; 18/024,471; 18/250,010; 19/473,423; 18/264,138; 19/162,722; and 17/996,878; the provisional nonstatutory double patenting rejections over the claims in these later-filed co-pending applications are still proper.
Regarding the Applicant’s argument that the Office improperly relies on secondary references to formulate the ODP rejections 14, 16, 17, and 22 in Table 1 because the secondary reference (Li) is not used by the Examiner to construe the claims, but rather to draw out disclosure of claim elements present in the currently pending claims in order to formulate the ODP rejections, which is the Applicant argues not permitted; note that in view of the similarities, the factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966) that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 should be considered when making a nonstatutory double patenting analysis based on "obviousness." See MPEP § 2141 for guidelines for determining obviousness. These factual inquiries are summarized as follows:
(A) Determine the scope and content of a patent claim relative to a claim in the application at issue;
(B) Determine the differences between the scope and content of the patent claim as determined in (A) and the claim in the application at issue;
(C) Determine the level of ordinary skill in the pertinent art; and
(D) Evaluate any objective indicia of nonobviousness.
Any nonstatutory double patenting rejection made under the obviousness analysis should make clear:
(A) The differences between the inventions defined by the conflicting claims — a claim in the patent compared to a claim in the application; and
(B) The reasons why a person of ordinary skill in the art would conclude that the invention defined in the claim at issue would have been an obvious variation of the invention defined in a claim in the patent.
Any secondary reference used to support an obviousness analysis for a nonstatutory double patenting rejection must be prior art under 35 U.S.C. 102 or pre-AIA 35 U.S.C. 102. See MPEP § 2120 et seq. for more information on determining if a reference is prior art and MPEP § 2141, subsection II.A, for determining the scope and content of the prior art. See MPEP 804II.B.3.
This applies to the instant case where the secondary references used in the obviousness-type nonstatutory double patenting rejections have been used to provide the motivation for combining what is taught by the instant claims with what is taught by the reference claims. Just as is the case for rejections under U.S.C. 103, the secondary reference is not used to construe the claims or draw out disclosure of claim elements present in the pending claims, but rather to provide a motivation/rationale for combining what is taught by the pending claims.
As such, the Examiner has indeed properly relied on Li as a secondary reference for each of rejections 14 (Reference Application No. 18/264,138 - the "'138 Application"), 16 & 17 (Reference Application No. 17/996,878 - the "'878 Application") and 22 (Reference Application No. 17/272,121 - the "'121 Application").
Regarding the Applicant’s arguments to NSDP rejection #s 14, 16, 17, and 22 that a person of skill in the art would not be motivated to substitute the second binding domain of anti-PD-1 bispecific antibodies taught by the reference claims with the anti-CTLA4 binding domain of the instant claims because the second binding domain are completely different with unique CDRs targeting completely different antigens; note that it would be obvious to one of ordinary skill in the art to apply the copending Applications’ anti-PD-1 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody. This is because the anti-PD-1 arm of Li et al.’s anti-PD-1/CTLA-4 bispecific antibody is identical to that of the reference claims and it has already been successfully applied in an anti-PD-1/CTLA-4 bispecific antibody.
Given that Li et al. teach a bifunctional antibody comprising a first functional area that targets PD-1 and a second function area that targets CTLA4; wherein the first functional area targeting PD-1 comprises identical CDRs to the reference claims’ anti-PD-1 antibody (instant SEQ ID NOs: 27-32) and the second function area targeting CTLA4 comprises the instantly claimed CDRs (instant SEQ ID NOs: 33-38); it would be obvious to a skilled artisan to apply the copending Applications’ anti-PD-1 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody with a reasonable expectation of success since it has already been done.
Therefore, the claims in the copending Applications would render the instant claims obvious.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
Regarding the Applicant’s that the present claims, in view of the amendment to claim 34 to recite that the heavy chain of the antibody comprises the heavy chain constant region mutations consisting only of L234A, L235A, and G237A according to the EU numbering system, are patentability distinct from the reference patents and applications used in rejections 17, 18, 19, 20, 21, 22 (17/996,878; US 11,578,128; 19/365,106; 11,479,608; 12,076,398; and 17/272,121); note that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03.
This applies to the instant case where claim 34 recites that the heavy chain constant region “comprises amino acid mutations consisting only of L234A, L235A, and G237A.” Therefore, given the broadest reasonable interpretation, the heavy chain may comprise additional mutations to the L234A, L235A, and G237A, such as those recited in McCarthy et al. (i.e. P238A, H268A, A330S and P331S).
The Applicant is invited to amend claim 34 to recite “wherein the heavy chain constant region consists of L234A, L235A, and G237A amino acid mutations according to the EU numbering system” in order to limit the claims to only these three mutations.
Regarding the request that that the Examiner reconsider the present rejection over the '458 Application in view of the arguments provided above regarding appropriate use of secondary references and the non-obviousness of the present claims over the cited art in the event that they are applicable to the unpublished claims of the '458 Application; the Examiner’s response to said arguments, as outlined above, still apply.
Therefore, the Applicant’s request to hold rejection 23 in Table 1 in abeyance until the '458 Application publishes and Applicant is able to evaluate the claimed subject matter is acknowledged.
Conclusion
No claims 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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 5:00 a.m. - 3:00 p.m. (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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