DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendment filed 12 June 2026 is acknowledged. Claims 1, 3-7, 10-15, 20, 24-25, and 28-31 have been cancelled. Claims 16, 17, 21, 22, 23, 33, 36-41 are amended. Claim 42 is new.
Election/Restriction
As previously described, the instant Application was subject to a species election for a single species of complete anti-TGF BRII binding domain comprising a full VH and VL or 3 HCDRs and 3 LCDRs and a single species of complete anti-PD-1 binding domain as defined by a full VH and VL or 3 HCDRs and 3 LCDRs. Applicant previously elected by telephone without traverse the anti-PD-1 binding domain comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 15, 16, and 17, respectively and a light chain variable domain comprising a CDR1, CDR2, and CDR3 having the amino acid sequences as set for in SEQ ID NOs: 49, AAS, and 51, respectively and a TGF-BRII binding domain comprising a heavy chain variable region comprising a CDR1, CDR2, and CDR3 having the amino acid sequences as set for in SEQ ID NOs: 24, 25, and 26, respectively and a light chain variable domain comprising a CDR1, CDR2, and CDR3 having the amino acid sequences as set for in SEQ ID NOs: 49, AAS, and 51, respectively (See Non-Final dated 3/12/2026 p. 4-5). Applicant has cancelled all but the elected species and has affirmed the species election in the Remarks (Remarks 6/12/2026 p. 15 Section X).
Claim Status
Claims 16-17, 21-23, 33, and 36-42 are pending and under examination in the instant office action.
Withdrawal of Objections
The objection warning to claim 28 that should claim 20 be found allowable, claim 28 would be objected to is moot due to the cancellation of claims 20 and 28.
The objection to claims 36 and 37 for reciting “a” multispecific antibody rather than “the” multispecific antibody is withdrawn in view of the amendments to the claims.
The objection to the specification for containing an embedded hyperlink is withdrawn in view of the amendments to the specification.
Withdrawal of Rejections
The rejections of claims 1, 3-7, 10-15, 20, 24-25, and 28-31 are moot in view of the cancellation of the claims.
The rejection of claims 17, 21-23, 37, 39, and 40 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendments to the claims.
The rejection of claims 1, 4-7, 10-12, 33, 36-37, and 41 under 35 U.S.C. 102(a)(2) as being anticipated by U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 is moot due to the cancellation or is withdrawn in view of the amendments to the claims.
The rejection of claims 24-25 under 35 U.S.C. 103 as being unpatentable over U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 is moot due to the cancellation of the claims.
The rejection of claims 1, 4-7, 10-17, 20-25, 28-31, 33, 36-41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11993654 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
The rejection of claim 3 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11993654 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020, as applied to claim 1 above, and in further view of Brinkmann, Ulrich, and Roland E. Kontermann. "The making of bispecific antibodies." MAbs. Vol. 9. No. 2. Taylor & Francis, 2017 is moot due to cancellation of the claims.
The provisional rejection of claims 1, 4-7, 10-17, 22-23, 33, 36-37, and 41 on the ground of nonstatutory double patenting as being unpatentable over claims 1-55 of copending Application No. 18633748 (reference application) is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
The provisional rejection of claim 3 on the ground of nonstatutory double patenting as being unpatentable over claim 1-55 of copending Application No. 18633748 as applied to claim 1 above and in further view of Brinkmann, Ulrich, and Roland E. Kontermann. "The making of bispecific antibodies." MAbs. Vol. 9. No. 2. Taylor & Francis, 2017 is moot due to cancellation of the claims.
The provisional rejection of claims 20-21, 24-25, 28-31, 38, 39, and 40 on the ground of nonstatutory double patenting as being unpatentable over claim 1-55 of copending Application No. 18633748 as applied to claims 1 and 16 above, and further in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
The provisional rejection of claims 1, 4-7, 10-17, 20-25, 28-31, 33, 36-41 on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, 21, 22, 28, 29, 45-48, and 50-66 of copending Application No. 17708901 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
The provisional rejection of claim 3 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11993654 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020, as applied to claim 1 above, and in further view of Brinkmann, Ulrich, and Roland E. Kontermann. "The making of bispecific antibodies." MAbs. Vol. 9. No. 2. Taylor & Francis, 2017 is moot due to cancellation of the claims.
The provisional rejection of 1, 4-7, 10-17, 20-25, 28-31, 33, 36-41 on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending app. no. 18625756 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 and U.S. Patent No. 11993654 to Plyte et. al. effectively filed 31 March 2021 is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
The provisional rejection of claim 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending app. no. 18625756 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 and U.S. Patent No. 11993654 to Plyte et. al. effectively filed 31 March 2021, as applied to claim 1 above, and in further view of Brinkmann, Ulrich, and Roland E. Kontermann. "The making of bispecific antibodies." MAbs. Vol. 9. No. 2. Taylor & Francis, 2017
The provisional rejection of claims 1, 4-7, 10-12, 24-25, 33, and 36 on the ground of nonstatutory double patenting as being unpatentable over claims 44-45, 57 90 of copending app. no. 17757953 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
The provisional rejection of claim on the ground of nonstatutory double patenting as being unpatentable over claim 57 of copending app. No. 17757953 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 as applied to claim 1 above and further in view of Brinkmann, Ulrich, and Roland E. Kontermann. "The making of bispecific antibodies." MAbs. Vol. 9. No. 2. Taylor & Francis, 2017.
The additional provisional NSDP rejections:
Copending Application No.:
Rejected over Application Claims:
SEQ ID NOs identical to instant SEQ ID NOs: 14, 23, and 48 (comprising instant CDRs 15, 16, 17; 24, 25, 26; and 49, 50, 52)
Application/Patent with similar (prov.) NSDP rejections:
18625703
46, 47, 52-73
SEQ ID NO: 6
N/A
SEQ ID NO: 16
U.S. Patent No. 11993654 in view of Desjarlais; Brinkmann
19466020
1-40
N/A
SEQ ID NO: 10, 36 (claim 9)
SEQ ID NO: 16 (claim 11)
Copending App. No. 1775793 in view of Desjarlais; Brinkmann; Plyte
is withdrawn in view of the amendments to the claims or moot due to cancellation of the claims.
Claim Interpretation
Instant claims 16, 17, 20, 21-25, 28-31, 38, and 40 each recite the phrase “having an amino acid sequence as set forth in SEQ ID NO:[…]” (emphasis is the Examiner’s). Because the specification makes it clear that it is the full sequences contemplated and not fragments of the sequences, the claims are interpreted to require the entirety of a recited sequence when they recite “having an amino acid sequence as set forth in SEQ ID NO:”.
Claim Rejections - 35 USC § 112(a)- Written Description- Maintained, modification necessitated by amendment
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 16-17, 21-23, 33, and 36-42 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 claims contain 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.
Regarding claims 16 and 38 the claims allow for changes to the CDR within the VH and VL (or complete VL exchange) of the antibody which is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the recited function of binding PD-1 and TGF-βRII.
Scope of the claimed genus
Claim 16 recites a multispecific binding moiety comprising a PD-1 binding domain and a TGF-βRII binding domain wherein the PD-1 binding domain comprises a heavy chain variable region defined by 3 CDRs (e.g. SEQ ID NOs: 15, 16, and 17, respectively) wherein each of the CDRs may comprise up to 3 amino acid variations and with an undefined light chain. Claim 38 recites a nucleic acid sequence encoding a heavy chain variable region of a PD-1 binding domain and a nucleic acid encoding a heavy chain variable region of a TGFBRII binding domain, wherein the TGF-ΒRII binding domain comprises a heavy chain variable region defined by CDRs (e.g. SEQ ID NOs: 24, 25, 26, respectively) wherein each of the CDRs may comprise up to three amino acid variations and with an undefined light chain.
Claims 33, 36, 37, and 41 depend from claim 16 without further limiting the antibody.
Claim 17 recites the MBM of Claim 16 wherein the PD-1 binding domain comprises a heavy chain variable region has at least 80% identity to SEQ ID NOs: 18; Claim 21 recites the a TGF-ΒRII binding domain defined by at least 80% identity to SEQ ID NOs: 23; Claim 22 recites the MBM wherein the PD-1 or the TGF-ΒRII binding domain comprises a light chain variable region comprising CDRs SEQ ID NOs: 49, 50, and 51 or a variant thereof; Claim 23 recites the MBM wherein the PD-1 or the TGF-ΒRII binding domain comprises a light chain variable region comprising a sequence 80% identical to SEQ ID NO: 48, but does not require the CDRs.
Thus, the scope of the claims is directed to anti-PD-1 and anti- TGF-βRII binding domains wherein the binding domains comprising less than 6 CDRs and with variants and substitutions in the CDR regions.
State of the Relevant Art
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. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1; PTO-892 3/12/2026). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80; PTO-892 3/12/2026) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” or “up to 3 amino acid variants” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language or up to 3 amino acid variants per CDR does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, up to 3 amino acids variants per CDR amounts to up to 9 substitutions in heavy chain CDRs out of about 40 residues, requiring only 77% identity to the CDRs of the anti-PD-1 binding domain comprising SEQ ID NOs: 15, 16, and 17, for example and only 74% identity to the CDRs of the anti-TGF-βRII binding domain comprising SEQ ID NOs: 24, 25, and 26.
Regarding the CDR variants with up to 3 amino acid substitutions per CDR, Dondelinger M, et. al. Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. 2018 Oct 16;9:2278. doi:10.3389/fimmu.2018.02278 (PTO-892 3/12/2026) teaches that even if contacting residues are known, all the residues of the CDR may be important for the antibody binding function: “Also, it should be noted that: (i) some contacting residues may contribute minimally to the binding free energy and even disfavor the complex formation and; (ii) that a residue energetically important for binding to the cognate antigen may not be important for the difference in affinity between cognate and non-cognate antigens and, finally; (iii) a residue crucial for antigen recognition may not be important for binding free energy”
It is therefore insufficient to recite only partial identities to only heavy chain CDRs in order to define an antigen binding domain.
In regards to anti-PD-1 and TGF-βRII antibodies, other anti-PD-1 antigen binding sites are known in the art. For example, the therapeutic antibody pembrolizumab also binds to PD-1, but comprises entirely different CDRs as shown in the alignment between the pembrolizumab heavy chain variable region (go.drunkbank.com DB09037; PTO-892 3/12/2026) and the instant heavy chain SEQ ID NO: 14 which do not show similarity:
RESULT 1
AASEQ2_03032026_191237
Query Match 56.7%; Score 389.5; DB 1; Length 120;
Best Local Similarity 58.3%;
Matches 77; Conservative 15; Mismatches 23; Indels 17; Gaps 2;
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTRFALHWVRQAPGQGLEWMGWIDPNTGTPTF 60
|||||||| |:||||||||||||||||||| : ::|||||||||||||| |:|: | |
Db 1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF 60
Qy 61 AQGVTGRFVFSLDTSVTTAYLQISSLKAEDTAVYYCAR-----SLGYCDSDICYPNWIFD 115
: | : |:| ||||::: ||: :||||||||| :| ||
Db 61 NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMG------------FD 108
Qy 116 NWGQGTLVTVSS 127
||||| |||||
Db 109 YWGQGTTVTVSS 120
In regards to anti- TGF-βRII antibodies, some of these are known in the art. For example, U.S. 20220144956 to Desjarlais et. al. (PTO-892 3/12/2026) teaches a bispecific antibody comprising a TGF-ΒRII binding domain comprising SEQ ID NO: 2389, which does not show similarity to the instant TGF-ΒRII heavy chain of SEQ ID NO: 23:
RESULT 1
AASEQ2_03032026_192336
Query Match 46.5%; Score 296.5; DB 1; Length 121;
Best Local Similarity 52.0%;
Matches 66; Conservative 16; Mismatches 34; Indels 11; Gaps 4;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFD--IYAMTWVRQAPGKGLEWVSVISGS---G 55
::|: ||| |||:| :| |:| || : :: |:|| |||||||: || |
Db 1 QLQVQESGPGLVKPSETLSLTCTVSGGSISNAYFSWGWIRQPPGKGLEWI----GSFYYG 56
Qy 56 GTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQG 115
| ||| |:| | ||| | ||| |:::|: | ||||||||| | | | ||||
Db 57 GKTYYNPSLKSRATISIDTSKNQFSLKLSSVTAADTAVYYCARGPTL--IRGVIDSWGQG 114
Qy 116 TLVTVSS 122
|||||||
Db 115 TLVTVSS 121
The state of the art therefore would require an artisan to screen each anti-PD-1 and anti-TGF-ΒRII binding domain because it would not be discernable a priori which sequence changes would maintain the current functions of blocking and binding to PD-1 and TGF-βRII. Further, the claims do not require that the binding domains be antibody binding domains, and would therefore require screening to determine which binding domains of any unknown structure (e.g. nucleic acid aptamers) perform the binding and blocking functions, or further the particular degree of binding and blocking functions required to get the functional results compared to controls antibodies that do not limit the instant binding domains.
Summary of Species disclosed in the original specification
The instant specification discloses 63 species of multispecific anti-PD-1 x anti- TGF-βRII binding molecules comprising 7 antibody-based anti-PD-1 antigen binding domains comprising heavy chain variable domains (VH) comprising SEQ ID NOs: 1, 5, 9, 13, 14, 18, 19 paired with a light chain variable domain (VL) comprising SEQ ID NO: 48 and 9 anti- TGF-βRII binding domains comprising VH comprising SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88,and 89 paired with a VL comprising SEQ ID NO: 48 (Table 1 p. 72). 35 of these multispecifics were tested in vitro in PD-1 SHP recruitment and NFAT reporter assays (Examples 2 and 3) and the pSMAD2/3 phosphorylation assay (Example 4, Table 4 and 5 p. 77).
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of 1) any binding domain of any macromolecule type that performs the claimed PD-1 and TGF-βRII blocking function and 2) variants to allow substitution, addition, or deletion of any amino acid in the CDRs of the claimed antibody-based antigen binding domains.
Are the disclosed species representative of the claimed genus?
MPEP 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The instant specification discloses 7 anti-PD-1 antigen binding domains and 9 anti- TGF-βRII domains each comprising a complete VH and VL, adequately describing 63 bispecific antibodies. Given the breadth of the genus potentially encompassing millions of multispecific binding moieties, even when restricted to multispecific antibodies with CDR substitution and swapping of heavy and light chain, an artisan would not understand the applicant to be in possession of the entire genus from the instant examples.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics (i.e. structure or other physical and/or chemical properties, by functional characteristics couples 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 claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed activity.
As noted above, the art identifies the CDRs as determining the binding of an antibody. The specification only discloses 7 anti-PD-1 binding domains and 9 anti-TGF-ΒRII binding domains. The art teaches that the required residues for binding of the anti-PD-1 antibody and of the anti- TGF-βRII antibody would be unpredictable. There are no alternate amino acid residues in the SEQ ID NOs of the VHs and VL disclosed.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein PD-1 or TGF-βRII. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 16 and 38 at the time of filing. Regarding claims 17, 21-23, 33, 36-37, and 39-42 the claims are ultimately dependent on the rejected claims 16 and 38 without narrowing the claimed subject matter and thus are also rejected.
Response to Arguments
Applicant’s arguments dated 6/12/2026 have been fully considered but are not persuasive. Applicant argues that the independent claims 16 and 38 have been amended to recite the CDRs of the heavy chain of the PD-1 binding domain and TGF-BRII binding domains which addresses the written description “by defining the claimed multispecific moieties in structural terms” (Remarks 6/12/2026 p. 9 and 10). Applicant further argues that sequence variation and substation of light chain is still allowed because the skilled artisan would be able to make such substitutions and determine whether the amended construct fell within the scope of the claims and that the artisan would be able to pair the heavy chain with a suitable light chain (Remarks 6/12/2026 p. 10 top). As described in the written description rejection above, MPEP §2163 states that written description may be fulfilled by “sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention”. MPEP §2163 further states “However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional”. When a genus is claimed, MPEP §2163 states: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021)”. The instant claims are directed to a genus of antibodies wherein the heavy chain of each antigen-binding domain may comprises up to 3 amino acid substitutions in each CDR and wherein the light chain of each antigen-binding domain may be completely exchanged for any light chain. As described in the written description rejection above, the instant specification discloses 63 species of multispecific anti-PD-1 x anti- TGF-βRII binding molecules comprising 7 antibody-based anti-PD-1 antigen binding domains comprising heavy chain variable domains (VH) comprising SEQ ID NOs: 1, 5, 9, 13, 14, 18, 19 paired with a light chain variable domain (VL) comprising SEQ ID NO: 48 and 9 anti- TGF-βRII binding domains comprising VH comprising SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88,and 89 paired with a VL comprising SEQ ID NO: 48 (Table 1 p. 72). 35 of these multispecifics were tested in vitro in PD-1 SHP recruitment and NFAT reporter assays (Examples 2 and 3) and the pSMAD2/3 phosphorylation assay (Example 4, Table 4 and 5 p. 77). Of these, 3 anti-PD-1 VHs fall within the scope of the instantly claimed anti-PD-1 HCDRs SEQ ID NO: 14 shares all of the same HCDRs and SEQ ID NO: 18, and SEQ ID NO: 19 comprises 1 amino acid change in the HCDR1, 2 within CDR2, and 2 within CDR3 as shown below:
SEQ5 QVQLQESGPGLVKPSETLSLTCTVSNGSLGFDFWSWIRQPPGRGLEWIGYIYY-SGSWSL 59
SEQ9 QVQLQESGPGLVKPSETLSLTCTVSDGSIGYHFWSWIRQPPGRGLEWIGYIVY-SGSYNV 59
SEQ13 QVQLQESGPGLVKPSETLSLTCTVSEGSIGYHFWSWIRQPPGRGLEWIGYIVY-SGSYNV 59
SEQ1 EVQLVQSGAEVKKPGSSMKVSCKASGGTFSSYVISWVRQAPGQGLEWMGMIIPVFDTSSY 60
SEQ14 QVQLVQSGSELKKPGASVKVSCKASGYTFTRFALHWVRQAPGQGLEWMGWIDPNTGTPTF 60
SEQ18 QVQLVQSGSELKKPGASVKVSCKASGYTFTRFALHWVRQAPGQGLEWMGWIDPNTGTPTF 60
SEQ19 QVQLVQSGSELKKPGASVKVSCKASGYTFTRFALSWVRQAPGQGLEWMGWIDPNTGTPTY 60
:*** :** : **. ::.::*..* :: *:** **:****:* * .: .
SEQ5 NPSFKGRVTMSVDTSKNQFSLNLRSVTAADTAVYYCARGGY-----TGYGGDWFDPWGQG 114
SEQ9 NPSLKTRVTMSVDTSKNQFSLNLRSVTAADTAVYYCARGGY-----TGYGGDWFDPWGQG 114
SEQ13 NPSLKTRVTMSVDTSKNQFSLNLRSVTAADTAVYYCARGGY-----TGYGGDWFDPWGQG 114
SEQ1 EKKFQGRITIIADKSTSTVYLELSSLRSEDAAVYYCARGT-------VEATLLFDFWGQG 113
SEQ14 AQGVTGRFVFSLDTSVTTAYLQISSLKAEDTAVYYCARSLGYCDSDICYPNWIFDNWGQG 120
SEQ18 AQGVTGRFVFSLDTSVTTAYLQISSLKAEDTAVYYCARSLGYCDSDICYPNWIFDNWGQG 120
SEQ19 AQDFTGRFVFSLDTSVTTAYLQISSLKAEDTAVYYCARSLGYCGSDICYPNGILDNWGQG 120
. *..: *.* . *:: *: : *:*******. :* ****
SEQ5 TLVTVSS 121
SEQ9 TLVTVSS 121
SEQ13 TLVTVSS 121
SEQ1 TLVTVSS 120
SEQ14 TLVTVSS 127
SEQ18 TLVTVSS 127
SEQ19 TLVTVSS 127
*******
Of the anti-TGFBRII VHs, SEQ ID NO: 23 and SEQ ID NO: 27 fall within the instantly claimed scope, with SEQ ID NO: 27 having one amino acid substitution in CDR1 relative SEQ ID NO: 23 as shown below:
SEQ31 QVQLVESGGGLVEPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVGRIKTTISGGAT 60
SEQ35 QVQLVESGGGLVEPGGSLRLSCAASGFKFSNAWMSWVRQAPGKGLEWVGRIKTTISGGAT 60
SEQ23 EVQLVESGGGLVQPGGSLRLSCAASGFTFDIYAMTWVRQAPGKGLEWVSVIS--GSGGTT 58
SEQ27 EVQLVESGGGLVQPGGSLRLSCAASGFTFDINAMTWVRQAPGKGLEWVSVIS--GSGGTT 58
SEQ39 QVQLVESGGGLVQPGGSLRLSCAVSGFTFRRYAMSWVRQAPGKGLEWVSAIS--ASGDRT 58
SEQ89 QVQLVESGGGLVQPGGSLRLSCAVSGFTFSRYAMSWVRQAPGKGLEWVSAIS--ASGDRT 58
SEQ88 QVQLVESGGGLVQPGGSLRLSCAVSGFTFSRYAMSWVRQAPGKGLEWVSAIS--ASGDRT 58
SEQ43 QVQLVESGGGLVQPGGSLRLSCAVSGFTFSRYAMSWVRQAPGKGLEWVSAIS--ASGDRT 58
SEQ47 QVQLVESGGGLVQPGGSLRLSCAVSGFTFSRYAMSWVRQAPGKGLEWVSAIS--ASGDRT 58
:***********:**********.***.* *:*************. *. **. *
SEQ31 DFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTL--------DLRDYWGQGTLV 112
SEQ35 QFAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTL--------DLRDYWGQGTLV 112
SEQ23 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLV 118
SEQ27 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQGTLV 118
SEQ39 HNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGIA-ASGKNYFDPWGQGTLV 117
SEQ89 KYTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKGTA-AAGKNYFDPWGQGTLV 117
SEQ88 KNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKGTA-AAGKNYFDPWGQGTLV 117
SEQ43 KNTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTA-AAGKNYFDPWGQGTLV 117
SEQ47 KYTDSVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYFCAKGTA-AAGKNYFDPWGQGTLV 117
: *****:****:************::******:*: . * *******
SEQ31 TVSS 116
SEQ35 TVSS 116
SEQ23 TVSS 122
SEQ27 TVSS 122
SEQ39 TVSS 121
SEQ89 TVSS 121
SEQ88 TVSS 121
SEQ43 TVSS 121
SEQ47 TVSS 121
****
As described in the “State of the Art” section above, it is not predictable a priori which CDRs can retain antigen binding when they are substituted, or which positions may be substituted and how, even for single amino acid changes to the CDR. Additionally, the instant claims are directed at both “VH-only” version of the multispecific antibody and substitution of any light chain. However, it was well known in the art at the time of filing that light chains were not dispensable for antigen binding in VH/VL antibodies. For example, Holliger P et al. (Nature Biotechnology 2005 23 1126–1136) teaches despite early excitement concerning the functional activity of single variable heavy domain antibodies, these antibody fragments rarely retained the affinity of the parent antibody and were also poorly soluble and often prone to aggregation (page 1127, left to right column bridging paragraph). Holliger teaches while high affinity single variable like domain antibodies are present in camelid, as VhH, and shark, as V-NAR, domains, these single domain antibodies are structurally different, wherein each display long surface loops, often larger than for conventional murine and human antibodies, and are able to penetrate cavities in target antigens, such as enzyme active sites (for example, lysozyme) and canyons in viral and infectious disease biomarkers (page 1127, left to right column bridging paragraph). Holliger teaches the structural changes are shown in Fig. 2, wherein superimposition of a human VH domain (Fig. 2b) and a single domain V-NAR(Fig. 2c) has a vastly different CDR3 that does not overlap structurally (Fig. 2d). Holliger teaches unlike mouse VH domains, camelid VhH and shark V-NAR domains are in general soluble and can be produced as stable in vitro targeting reagents (page 1127, right column, second paragraph). Thus, single-domain antibodies are not generally only a VH or VL and antibodies and require both the VH and VL, which are distinct from VHH.
It is also well known in the art that different light chain CDRs may entirely alter the binding of the VH/VL antibody. For example, U.S. 20170355756 to Julien teaches an antibody specific for human TDP-43 comprising 3 CDRs termed “C10-VH3” (Table A, SEQ ID NO: 4). WO2008068048 to Cassone teaches an antibody with a heavy chain comprising 3 identical CDRs (“αSAP 2A8”; p. 18, SEQ ID NO: 2). However, the antibody of Cassone is paired with a different VL and targets an entirely different protease secreted aspartyl protease (SAP) from pathogenic yeast in the genus Candida sp. Thus, a person of ordinary skill in the art would not at once have been able to envision the entire genus of variants that are within the scope of the instant claims. The Examiner suggests obviating this rejection by claiming complete sets of 6 CDRs for each binding domain of the multispecific antibody for each variant demonstrated in the specification to specifically bind PD-1 or TGFBRII.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement- Maintained, changes necessitated by amendment
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 16-17, 21-23, 33, and 36-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
multispecific binding moiety comprising a PD-1 binding domain and a TGF-ΒRII binding domain wherein the PD-1 binding domain blocks PD-1 mediated signaling and the TGF-ΒRII binding domain blocks TGF-ΒRII-mediated signaling wherein the TGF-ΒRII and PD-1 binding domains each comprise an antibody binding domain comprising a complete variable heavy and variable light chain;
the multispecific antibody of (i) wherein the antibody has higher activity in reducing tumor volume than a combination of reference antibodies as defined in claim 13 and wherein the PD-1 binding domain comprises the particular CDRs of one of a)-e) as set forth in claim 16 and the TGF-ΒRII binding domain comprises the particular CDRs of one of a)-g) as set forth in claim 20;
a method for treating a cancer that expresses TGF-ΒRII comprising administering an effective amount of a multispecific binding moiety as described in i-ii) above
a cell comprising a nucleic acid sequence encoding a heavy chain variable region and a light chain variable region of a PD-1 binding domain as defined in (i) and encoding a heavy chain variable region and a light chain variable region of a TGF-ΒRII binding domain as defined in (i)
does not reasonably provide enablement for:
multispecific binding moieties comprising PD-1 binding domain that blocks PD-1 mediated signaling and TGF-ΒRII binding domain that blocks TGF-ΒRII mediated signaling that comprising one, two, or three amino acid substitutions in each HCDR and with only a heavy chain;
generic multispecific binding moieties possessing the particular functional characteristics of claims 4-7 and 10-15 such as higher activity in reducing tumor volume than the particular combination of monospecific antibodies;
a method of treating a generic disease or a generic disease “associated with suppressed immune system” in a subject in need thereof comprising administering an effective amount of the generic multispecific binding moiety;
a cell comprising a nucleic acid encoding only the heavy chains of the multispecific binding moiety with no light chain as recited in claim 38.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method of the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(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.
The following is an analysis of these factors in relationship to this application.
Scope of the claims and nature of the invention
Claim 16 recites a multispecific binding moiety comprising a PD-1 binding domain and a TGF-βRII binding domain wherein the PD-1 binding domain comprises a heavy chain variable region defined by 3 CDRs (e.g. SEQ ID NOs: 15, 16, and 17, respectively) wherein each of the CDRs may comprise up to 3 amino acid variations and with an undefined light chain. Claim 38 recites a nucleic acid sequence encoding a heavy chain variable region of a PD-1 binding domain and a nucleic acid encoding a heavy chain variable region of a TGFBRII binding domain, wherein the TGF-ΒRII binding domain comprises a heavy chain variable region defined by CDRs (e.g. SEQ ID NOs: 24, 25, 26, respectively) wherein each of the CDRs may comprise up to three amino acid variations and with an undefined light chain.
Claims 33, 36, 37, and 41 depend from claim 16 without further limiting the antibody.
Claim 17 recites the MBM of Claim 16 wherein the PD-1 binding domain comprises a heavy chain variable region has at least 80% identity to SEQ ID NOs: 18; Claim 21 recites the a TGF-ΒRII binding domain defined by at least 80% identity to SEQ ID NOs: 23; Claim 22 recites the MBM wherein the PD-1 or the TGF-ΒRII binding domain comprises a light chain variable region comprising CDRs SEQ ID NOs: 49, 50, and 51 or a variant thereof; Claim 23 recites the MBM wherein the PD-1 or the TGF-ΒRII binding domain comprises a light chain variable region comprising a sequence 80% identical to SEQ ID NO: 48, but does not require the CDRs.
Thus, the scope of the claims is directed to anti-PD-1 and anti- TGF-βRII binding domains wherein the binding domains comprising less than 6 CDRs and with variants and substitutions in the CDR regions.
State of the Relevant Art; level of ordinary skill; and level of predictability in the art
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. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1; PTO-892 3/12/2026). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80; PTO-892 3/12/2026) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” or “up to 3 amino acid variants” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language or up to 3 amino acid variants per CDR does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, up to 3 amino acids variants per CDR amounts to up to 9 substitutions in heavy chain CDRs out of about 40 residues, requiring only 77% identity to the CDRs of the anti-PD-1 binding domain comprising SEQ ID NOs: 15, 16, and 17, for example and only 74% identity to the CDRs of the anti-TGF-ΒRII binding domain comprising SEQ ID NOs: 24, 25, and 26.
Regarding the CDR variants with up to 3 amino acid substitutions per CDR, Dondelinger M, et. al. Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. 2018 Oct 16;9:2278. doi:10.3389/fimmu.2018.02278 (PTO-892 3/12/2026) teaches that even if contacting residues are known, all the residues of the CDR may be important for the antibody binding function: “Also, it should be noted that: (i) some contacting residues may contribute minimally to the binding free energy and even disfavor the complex formation and; (ii) that a residue energetically important for binding to the cognate antigen may not be important for the difference in affinity between cognate and non-cognate antigens and, finally; (iii) a residue crucial for antigen recognition may not be important for binding free energy”
It is therefore insufficient to recite only partial identities to only heavy chain CDRs in order to define an antigen binding domain.
In regards to anti-PD-1 and TGF-ΒRII antibodies, other anti-PD-1 antigen binding sites are known in the art. For example, the therapeutic antibody pembrolizumab also binds to PD-1, but comprises entirely different CDRs as shown in the alignment between the pembrolizumab heavy chain variable region (go.drunkbank.com DB09037; PTO-892 3/12/2026) and the instant heavy chain SEQ ID NO: 14 which do not show similarity:
RESULT 1
AASEQ2_03032026_191237
Query Match 56.7%; Score 389.5; DB 1; Length 120;
Best Local Similarity 58.3%;
Matches 77; Conservative 15; Mismatches 23; Indels 17; Gaps 2;
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTRFALHWVRQAPGQGLEWMGWIDPNTGTPTF 60
|||||||| |:||||||||||||||||||| : ::|||||||||||||| |:|: | |
Db 1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF 60
Qy 61 AQGVTGRFVFSLDTSVTTAYLQISSLKAEDTAVYYCAR-----SLGYCDSDICYPNWIFD 115
: | : |:| ||||::: ||: :||||||||| :| ||
Db 61 NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMG------------FD 108
Qy 116 NWGQGTLVTVSS 127
||||| |||||
Db 109 YWGQGTTVTVSS 120
In regards to anti-TGF-ΒRII antibodies, some of these are known in the art. For example, U.S. 20220144956 to Desjarlais et. al. (PTO-892 3/12/2026) teaches a bispecific antibody comprising a TGF-ΒRII binding domain comprising SEQ ID NO: 2389, which does not show similarity to the instant TGF-ΒRII heavy chain of SEQ ID NO: 23:
RESULT 1
AASEQ2_03032026_192336
Query Match 46.5%; Score 296.5; DB 1; Length 121;
Best Local Similarity 52.0%;
Matches 66; Conservative 16; Mismatches 34; Indels 11; Gaps 4;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFD--IYAMTWVRQAPGKGLEWVSVISGS---G 55
::|: ||| |||:| :| |:| || : :: |:|| |||||||: || |
Db 1 QLQVQESGPGLVKPSETLSLTCTVSGGSISNAYFSWGWIRQPPGKGLEWI----GSFYYG 56
Qy 56 GTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGQYRDIVGATDYWGQG 115
| ||| |:| | ||| | ||| |:::|: | ||||||||| | | | ||||
Db 57 GKTYYNPSLKSRATISIDTSKNQFSLKLSSVTAADTAVYYCARGPTL--IRGVIDSWGQG 114
Qy 116 TLVTVSS 122
|||||||
Db 115 TLVTVSS 121
The state of the art therefore would require an artisan to screen each anti-PD-1 and anti-TGF-ΒRII binding domain because it would not be discernable a priori which sequence changes would maintain the current functions of blocking and binding to PD-1 and TGF-ΒRII. Further, the claims do not require that the binding domains be antibody binding domains, and would therefore require screening to determine which binding domains of any unknown structure (e.g. nucleic acid aptamers) perform the binding and blocking functions, or further the particular degree of binding and blocking functions required to get the functional results compared to controls antibodies that do not limit the instant binding domains.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification discloses 63 species of multispecific anti-PD-1 x anti-TGF-ΒRII binding molecules comprising 7 antibody-based anti-PD-1 antigen binding domains comprising heavy chain variable domains (VH) comprising SEQ ID NOs: 1, 5, 9, 13, 14, 18, 19 paired with a light chain variable domain (VL) comprising SEQ ID NO: 48 and 9 anti-TGF-ΒRII binding domains comprising VH comprising SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88,and 89 paired with a VL comprising SEQ ID NO: 48 (Table 1 p. 72). 35 of these multispecifics were tested in vitro in PD-1 SHP recruitment and NFAT reporter assays (Examples 2 and 3) and the pSMAD2/3 phosphorylation assay (Example 4, Table 4 and 5 p. 77). In the in vivo assay against MDA-MB-231 xenograft model in huCD34 NSG mice, 3 particular bispecifics of SEQ ID NO: 43 x SEQ ID NO: 9 (both 1 and 10
One of skill in the art would reasonably conclude that it would take undue experimentation to determine which of the millions of multispecific binding moieties comprising or variants of the heavy chain comprising up to 3 mutations per CDR and any light chain variant as claimed, or which generic diseases or diseases associated with suppression of immune function may be treated, or to make and use cells comprising the heavy chains with up to 3 CDR mutations and with any light chain variant as claimed.
Conclusion
The Applicant does not have enablement for the multispecific binding moieties, the multispecific binding moieties with the particular functional properties, cells comprising nucleic acids encoding the multispecific binding moieties, and the methods of treating as claimed. It would take undue experimentation to make and use the multispecific binding moieties consonant with the entire scope of the instant claims.
Response to Arguments
Applicant’s arguments dated 6/12/2026 have been fully considered but are not persuasive. Applicant argues that claim 16 still allows for sequence variation and does not recite the light chain CDRs because a skilled person would be able to make such substitutions and determine whether the substituted construct fell within the scope of the claims without undue experimentation and would be able to pair the construct with a suitable light chain such as a common light chain (Remarks 6/12/2026 p. 10). MPEP §2164 states that the factors to be considered to determine whether a claim is enabled are:
(A) The breadth of the claims; [AltContent: rect]
(B) The nature of the invention; [AltContent: rect]
(C) The state of the prior art; [AltContent: rect]
(D) The level of one of ordinary skill; [AltContent: rect]
(E) The level of predictability in the art; [AltContent: rect]
(F) The amount of direction provided by the inventor; [AltContent: rect]
(G) The existence of working examples; and [AltContent: rect]
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP 2164 further states that “representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art (in view of level of skill, state of the art and the information in the specification) would expect the claimed genus could be used in that manner without undue experimentation”. As described in the scope of enablement rejection above, although the level of skill in the art is high, the unpredictability of the art of antibodies is also very high. As described in the state of the art section above, a person of ordinary skill in the art “cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains” (MPEP 2164) and therefore each change to any of the 6 CDRs of the antibody (including amino acids in the HCDRs or any changes to the light chain as permitted by the instant claims) must be tested individually in order to determine whether it maintains the instantly claimed binding functions. Since any light chain at all may be permitted by the scope of the claims, the scope encompasses millions of potential antibodies for each binding domain. For example, in regard to only the PD-1 heavy chain, 3 variations in the CDR1, the CDR2, or the CDR3 with only substitutions to standard amino acids, no additions or deletions, allows for 20 possibilities at 3 positions with the other 2 positions locked
5
0
x
19
0
+
5
1
x
19
1
+
5
2
x
19
2
+
5
3
x
19
3
= 72,296 combinations just for HCDR1 alone. Each of these CDR1s would then be multiplied by all of the possible HCDR2, HCDR3, and light chain CDR variants to arrive at all the antibodies claimed just for one of the antigen binding domains. Because each of these antibodies (each combination of 6 CDRs) would need to be independently screened for the claimed binding functions to PD-1 and TGFBRII due to the unpredictability of the art as described, the small number of examples given and guidance given by the instant inventors as described in the scope of enablement rejection above is insufficient to overcome the burden that this amount of screening would create. When taken as a whole, the scope of the claims, nature of the invention, level of skill of the artisan, level of predictability in the art, amount of direction provided by the inventor, and the working examples would leave ordinary artisans with an undue burden to determine which of the millions (or more) potential multispecific antibodies meet the functional limitations of the instant claims.
Claim Rejections - 35 USC § 103- Maintained, changes necessitated by amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 16, 17, 21-23, 33, and 36-42 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 (PTO-892 dated 3/12/2026) in view of U.S. 11993654 to Plyte et. al. effectively filed 31 March 2021.
The applied reference (U.S. 11993654 to Plyte et. al.) has a common Assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Desjarlais et. al. teaches a bispecific antibody that binds to TGF-ΒRII and PD-1 blocks the activity of TGFB (Abstract). Desjarlais teaches that one embodiment of the bispecific antibody is an anti-PD-1 mAb “based on nivolumab” [0052]; Desjarlais teaches “PD1 binding domains which do compete for binding with PD-1 blockade antibodies such as nivolumab and pembrolizumab may still be suitable for use in the anti-TGFßRII×anti-PD1 bsAbs. Accordingly, additional PD1 binding domains contemplated for use are depicted as SEQ ID NOs: 131-482” [0377] and that “mAb B and mAb C are partial blockers of the PD-1:PD-L1 interaction” [0376].
Desjarlais et. al. teaches the bispecific antibody (reads on multispecific binding moiety, MBM) wherein “blocking experiments were performed utilizing unactivated (PD1 low) and activated PBMCs (PD1 high). For experiments utilizing unactivated PBMCs, PBMCs were thawed and recovered overnight for 24 hours, then serum deprived for 16 hours (in 0.1% FBS). In experiments utilizing activated PBMCs, PBMCs were activated by seeding on 0.5 μg/ml anti-CD3 for 48 hours, then serum deprived for 16 hours (in 0.1% FBS). In both types of experiments, following serum deprivation, PBMCs were incubated with the test articles at indicated concentrations for 30 minutes at room temperature followed by incubation with the test articles+1 ng/ml TGFß1 for 30 minutes at 37° C. The data as depicted in FIG. 57 show that blocking activity is highly selective for activated (PD1-high) T cells over unactivated (PD1-low) T cells” [0389]. Fig. 57 shows that % maximal TGFb1-induced pSMAD2 in CD4+ and CD8+ T cells is about 200 fold greater in PD-1-high cells than PD-1-low cells.
Desjarlais et. al. teaches a bivalent monospecific antibody anti-TGF-ΒRII, for example XENP28297 comprising SEQ ID NO: 1886 (100% identical to instant SEQ ID NO: 77) and SEQ ID NO: 1885 (98.4% identical to instant SEQ ID NO: 76 with modification to the IgG1 domain as shown below):
ALIGN
ALIGNMENT FROM L-NUMBER L4
Query Length: 451; Sequence Length: 450;
Score: 883.2 bits (2281), 98.2% of highest possible score 899.4;
Expect value: 1.224e-254;
Identities: 444 / 451 (98.4%); Positives: 447 / 451 (99.1%);
Query Identity: 98.4%; Query Coverage: 100.0%;
Subject Identity: 98.7%; Subject Coverage: 100.0%;
Alignment Length: 451;
Q: 1 QLQVQESGPGLVKPSETLSLTCTVSGGSISNSYFSWGWIRQPPGKGLEWIGSFYYGEKTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
S: 1 QLQVQESGPGLVKPSETLSLTCTVSGGSISNSYFSWGWIRQPPGKGLEWIGSFYYGEKTY 60
Q: 61 YNPSLKSRATISIDTSKSQFSLKLSSVTAADTAVYYCPRGPTMIRGVIDSWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||+|||||||||||||||||
S: 61 YNPSLKSRATISIDTSKSQFSLKLSSVTAADTAVYYCPRGPTVIRGVIDSWGQGTLVTVS 120
Q: 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
S: 121 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS 180
Q: 181 SGlyslssvvtvpssslGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLG 240
|||||||||||||||||||||||||||||||||||||+|||||||||||||||||| +
S: 181 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPP-VA 239
Q: 241 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 300
|||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||
S: 240 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEQY 299
Q: 301 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
S: 300 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE 359
Q: 361 EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
S: 360 EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 419
Q: 421 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 451
|||||||||||||||||||||||||||||||
S: 420 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 450
Desjarlais teaches that XENP28297 has an EC50 of approximately 3ng/mL and a maximum activation of about 50% B cells, whereas the PD1xTGF-ΒRII bispecifics have EC50s with TBRII-B and A binding domains have EC50s of ~50 and ~1.7, respectively with maximum activation of approximately 20% and approximately 30%, respectively (See Fig. 30A-B) and an EC50 of about 1ng/ml and a maximum activation of about 60% T cells, whereas the PD1xTGF-ΒRII bispecifics have EC50s haves EC50s of ~40 and ~7, respectively with maximum activation of approximately 10% and approximately 50% “The data as depicted in FIG. 28-31 show that the anti-TGFßRII×anti-PD1 bsAbs blocked TGFß1 activity as indicated by decreased potency of TGFß1 in inducing SMAD2/3 phosphorylation following incubation with the bsAbs. Notably, the anti-TGFßRII×anti-PD1 bsAbs having anti-TGFßRII arms based on TBRII-A and TBRII-B show superior blocking of TGFß1-induced SMAD2/3 phosphorylation on CD4+ and CD8+ T cells compared to corresponding anti-TGFßRII mAbs and anti-TGFßRII×anti-RSV bsAbs indicating that the PD-1-targeting enhances the blocking activity. However, the PD-1 targeting effect was less pronounced/non-existent in B cells and NK cells. Surprisingly, the TGFßRII binding domain TBRII-C was unable to block TGFß1-induced SMAD2/3 phosphorylation both in the context of a bivalent mAb and in the context of an anti-TGFßRII×anti-PD1 bsAb indicating that not all TGFßRII binders are able to block the activity of TGFß” [0382].
Desjarlais discloses pharmaceutical compositions comprising the antibodies and pharmaceutically acceptable carriers [0359].
Desjarlais discloses a method of treating cancer comprising administering to a mouse xenograft model using pp65-transduced MDA-MB231 cancer cells the bispecific antibody comprising the anti-PD-1 and anti-TGF-ΒRII blocking domains (Example 4.2 [0394-0398], Fig. 39-40). Desjarlais teaches a host cell comprising a nucleic acid used to produce the heterodimeric antibodies of the invention [0355, 0358] (reads on “a cell producing the multispecific binding moiety of claim 1).
Desjarlais et. al. does not teach an MBM comprising a PD-1 binding domain and a TGFRBII binding domain wherein the PD-1 binding domain comprises HCDRs1-3 of SEQ ID NO: 15, 16, and 17, respectively (claim 16); wherein the PD-1 binding domain comprises a heavy chain variable regions having at least 80% identical to SEQ ID NO: 14 (claim 17, 29); wherein the PD-1 binding domain and/or the TGF-ΒRII binding domain comprises a light chain variable region comprising SEQ ID NOs: 49, 50, 51 (claim 22, 30) or VL SEQ ID NO: 48 (claim 23, 31); wherein the PD-1 binding domain comprises SEQ ID NO: 15, 16, and 17 and the TGF-ΒRII binding domain comprises SEQ ID NOs; 24, 25, and 26 (claims 20, 28) or the VH SEQ ID NO: 23 (claim 22); a cell comprising a nucleic acid sequence encoding the heavy chain variable region of a PD-1 binding domain as defined in claim 16 and a nucleic acid sequence encoding the TGF-ΒRII binding domains comprising SEQ ID NOs: 24, 25, and 26 (claim 38) and further comprising a nucleic acid sequence a CH1 region (claim 39) and further comprising at least one nucleic acid encoding a light chain variable region comprising SEQ ID NO: 49, 50, and 5 (claim 40).
This deficiency is resolved by Plyte et. al.
Plyte et. al. teaches PD-1 binding domains that have a higher affinity for human PD-1 than a reference PD-1 binding domain and having equal or higher potency in blocking ligand binding to PD-1 than a reference antibody, and binding moieties comprising such PD-1 binding domains (Abstract). Plyte et. al. teaches a that the PD-1 binding domain comprises a VH SEQ ID NO: 5 (claims 2 and 3) (100% identical to instant SEQ ID NO: 14 and comprising CDRs instant SEQ ID NOs: 15, 16, and 17) and a VL SEQ ID NO: 16 (claims 5-7) 100% identical to instant SEQ ID NO: 48 and comprising instant CDRs SEQ ID NOs: 49, AAS, and 51). Plyte et. al. teaches that the light chain SEQ ID NO: 16 comprising CDRs 49, AAS, and 51 is a common light chain capable of pairing with multiple different heavy chain which is particularly useful in the generation of bispecific antibodies (Col. 11 lines 24-41). Plyte et. al. teaches that one embodiment of the invention is a multispecific binding moiety comprising at least two binding domains which have specificity for at least two targets or epitopes (Col. 13 line 61- Col. 14 line 5).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make a bispecific antibody comprising the anti-PD-1 binding domain comprising SEQ ID NO: 5 and SEQ ID NO: 16 as taught by Plyte et. al. to benefit from the strong anti-PD-1 binding and blocking as taught by Plyte and the common light chain of SEQ ID NO: 16 in an anti-PD-1/anti-TGF-ΒRII bispecific as taught by Desjarlais et. al. and further comprising the anti-TGF-ΒRII binding domain comprising VH SEQ ID NO: 990 and VL SEQ ID NO: 1315 to benefit from making a bispecific with identical common light chains Desjarlais SEQ ID NO: 1315 and Plyte SEQ ID NO: 16 in order to more efficiently make a bispecific; and further because Desjarlais et. al. teaches that targeting PD-1 and TGF-ΒRII makes an efficacious anti-cancer bispecific antibody. This would have a reasonable expectation of success because methods of making bispecific antibodies with a common light chain were known in the art as taught by Desjarlais et. al. and Plyte et. al.
Regarding claim 16, as evidenced by the instant specification Fig. 9F, the antibody of modified Desjarlais et. al. in view of Plyte which has the same sequences as the instant antibody would inherently have the same functions and therefore possess identical functional characteristics.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Response to Arguments
Applicant’s arguments dated 6/12/2026 have been fully considered but are not persuasive. In regard to the rejection under 35 U.S.C. 102(a)(1) as being anticipated by Desjarlais and the 103 rejection of claims 24-25 as being obvious in view of Desjarlais, these rejections and arguments are moot in view of the cancellation and amendment of the claims.
Regarding the rejection of Desjarlais in view of Plyte, Applicant argues that “there was no motivation in the prior art to modify the TGF-BRII x PD-1 antibodies disclosed in Desjarlais because there was no objective reason to combine. Applicant further argues that “even if a skilled person were motivated to replace the PD-1 arm of Desjarlais bispecific antibody, there is no teaching or suggestion that would have led them to select the specific PD-1 binding domain of Plyte. This is not persuasive. MPEP §2144.06 teaches that substituting art-known equivalents for the same purpose is prima facie obvious and an express suggestion to substitute one equivalent for another is not necessary to render the substitution obvious. As described in the 103 rejection above, the anti-PD-1 antibody of Desjarlais and the anti-PD-1 antibody of Plyte were art known-equivalents because both antibodies are PD-1 antibodies for blocking ligand binding to PD-1 and both are disclosed as useful for purpose in the context of a PD-1 blocking bispecific antibody. Even further, as described in the 103 rejection above, there was additional motivation to combine the two antibodies comprising the exact same light chain because both Plyte and Desjarlais teach making bispecific antibodies with common light chains and a person of ordinary skill in the art would understand from the sequences of the anti-PD-1 antibodies of Plyte and the anti-TGFBRII antibodies of Desjarlais that they share a light chain and therefore would be suitable for making a multispecific antibody with a common light chain.
Double Patenting- New/modified, necessitated by amendment
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.
U.S. Patent No. 11993654
Claims 16-17, 21-23, 33, and 36-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11993654 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 (PTO-892 dated 3/12/2026).
The ‘654 patent et. al. teaches PD-1 binding domains wherein the PD-1 binding domain comprises a VH SEQ ID NO: 5 (claims 2 and 3) (100% identical to instant SEQ ID NO: 14 and comprising CDRs instant SEQ ID NOs: 15, 16, and 17) and a VL SEQ ID NO: 16 (claims 5-7) 100% identical to instant SEQ ID NO: 48 and comprising instant CDRs SEQ ID NOs: 49, AAS, and 51).
The ’654 patent is not directed explicitly directed towards a multispecific binding moiety (MBM) wherein the MBM comprises the anti-PD-1 binding domain of ‘654 and an anti-TGF-ΒRII binding domain; and wherein the anti-TGF-ΒRII binding domain comprises HC SEQ ID NO: 23 or CDRs SEQ ID NOs: 24, 25, and 26.
This deficiency is resolved by Desjarlais et. al. The teachings of Desjarlais et. al. are in the 103 rejection above. Briefly, Desjarlais et. al. teaches anti-PD-1 and anti-TGF-ΒRII bispecific antibodies that block PD-1 and TGF-ΒRII and further suggests an anti-TGF-ΒRII binding domain SEQ ID NO: 990, which is 100% identical to instant SEQ ID NO: 23 and comprises instant CDRs SEQ ID NOs: 24, 25, and 26, respectively ([0007], [0034-0036], [0265-0270]). Desjarlais teaches a light chain of the TGF-ΒRII binding domain comprising SEQ ID NO: 1315 which is 100% identical to instant SEQ ID NO: 48 and comprises instant CDRs SEQ ID NOs: 49, 50, and 51 ([0007], [0036], [0266-0270]). Regarding claim 38, Desjarlais teaches a host cell comprising a nucleic acid used to produce the heterodimeric antibodies of the invention [0355, 0358].
It would have been obvious for a person of ordinary skill in the art to make a bispecific antibody comprising the anti-PD-1 binding domain comprising SEQ ID NO: 5 and SEQ ID NO: 16 as taught by ‘654 patent et. al. to benefit from the strong anti-PD-1 binding and blocking as taught by ‘654 patent and the common light chain of SEQ ID NO: 16 in an anti-PD-1/anti-TGF-ΒRII bispecific as taught by Desjarlais et. al. and further comprising the anti-TGF-ΒRII binding domain comprising VH SEQ ID NO: 990 and VL SEQ ID NO: 1315 to benefit from making a bispecific with the identical common light chains Desjarlais SEQ ID NO: 1315 and ‘654 patent SEQ ID NO: 16 in order to more efficiently make a bispecific antibody comprising two Fab domains; and further because Desjarlais et. al. teaches that targeting PD-1 and TGF-ΒRII makes an efficacious anti-cancer bispecific antibody. This would have a reasonable expectation of success because methods of making bispecific antibodies with the common light chain were known in the art as taught by Desjarlais et. al.
Copending App. No. 18633748
Claims 16-17, 21-23, 33, and 36-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-55 of copending Application No. 18633748 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 (PTO-892 dated 3/12/2026).
This is a provisional nonstatutory double patenting rejection.
The claims of ‘748 recite a method of treating a disorder in a human subject in need thereof, wherein the disorder is selected from a group of cancer, wherein the method comprises administering to the human subject a therapeutically effective amount of a bispecific antibody that binds to human PD-1 and human TGFBR2 wherein the bispecific antibody comprises an anti-human PD1 binding domain comprising a heavy chain and a light chain variable region comprising HCDRs SEQ ID NOs: 1-3 identical to instant SEQ ID NOs: 15, 16, and 17 and LCDRs SEQ ID NOs: 11-13 identical to instant SEQ ID NOs: 49, AAS, and 51 and wherein the anti-human TGFBR2 binding domain comprises a heavy chain and a light chain variable region comprising HCDRs SEQ ID NOs: 6-8 and LCDRs SEQ ID NOs: 11-13 identical to SEQ ID NOs: 49, AAS, and 51.
The claims of the ‘784 application do not teach a bispecific antibody that binds to human PD-1 and human TGFBR2 wherein the bispecific antibody comprises a TGFBR2 binding domain comprising HCDRs of SEQ ID NOs: 24, 25, and 26, respectively.
This deficiency is resolved by Desjarlais et. al. The teachings of Desjarlais et. al. are in the 103 rejection above. Briefly, Desjarlais et. al. teaches a bispecific antibody that binds to TGF-ΒRII and PD-1 blocks the activity of TGFB and PD-1 (Abstract, [0376-0377]). Desjarlais et. al. teaches a list of potential anti-TGF-ΒRII binding domains including SEQ ID NO: 990, which is 100% identical to instant SEQ ID NO: 23 and comprises instant CDRs SEQ ID NOs: 24, 25, and 26, respectively ([0007], [0034-0036], [0265-0270]). Desjarlais teaches a light chain of the TGF-ΒRII binding domain comprising SEQ ID NO: 1315 which is 100% identical to instant SEQ ID NO: 48 and comprises instant CDRs SEQ ID NOs: 49, 50, and 51 ([0007], [0036], [0266-0270]). Regarding claim 38, Desjarlais teaches a host cell comprising a nucleic acid used to produce the heterodimeric antibodies of the invention [0355, 0358].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make a bispecific antibody as taught by Desjarlais comprising a PD-1 binding domain and a TGF-ΒRII binding domain comprising SEQ ID NO: 990 and SEQ ID NO: 1315 as taught by Desjarlais in order to benefit from a particular embodiment of the anti-PD-1/anti-TGF-ΒRII multidomain antibody as taught by Desjarlais as suitable for the anti-PD-1/anti-TGF-ΒRII bispecific anti-tumor activity. This would have a reasonable expectation of success because Desjarlais teaches a list of particular embodiments for the TGF-ΒRII binding domain and a series of alternate formats, and a person of ordinary skill in the art would expect to be able to make an embodiment with anti-PD-1 and anti-TGF-ΒRII binding by substituting out the domains disclosed as equivalent anti-TGF-ΒRII binders by Desjarlais.
Copending App. No. 17708901
Claims 16-17, 21-23, 33, and 36-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, 21, 22, 28, 29, 45-48, and 50-66 of copending Application No. 17708901 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 (PTO-892 dated 3/12/2026).
The ‘901 patent teaches a multispecific binding moiety comprising PD-1 binding domains wherein the PD-1 binding domain comprises a VH SEQ ID NO: 5 (claims 2 and 3) (100% identical to instant SEQ ID NO: 14 and comprising CDRs instant SEQ ID NOs: 15, 16, and 17) and a VL SEQ ID NO: 16 (claims 5-7) 100% identical to instant SEQ ID NO: 48 and comprising instant CDRs SEQ ID NOs: 49, AAS, and 51) and a LAG-3 binding domain comprising a light chain comprising SEQ ID NO: 24, 100% identical to instant SEQ ID NO: 48.
The ’901 patent does not teach a multispecific binding moiety (MBM) wherein the MBM comprises the anti-PD-1 binding domain of ‘901 and an anti-TGF-ΒRII binding domain; and wherein the anti-TGF-ΒRII binding domain comprises HC SEQ ID NO: 23 or CDRs SEQ ID NOs: 24, 25, and 26.
This deficiency is resolved by Desjarlais et. al. The teachings of Desjarlais et. al. are in the 103 rejection above. Briefly, Desjarlais et. al. teaches anti-PD-1 and anti-TGF-ΒRII bispecific antibodies that block PD-1 and TGF-ΒRII and further suggests an anti-TGF-ΒRII binding domain SEQ ID NO: 990, which is 100% identical to instant SEQ ID NO: 23 and comprises instant CDRs SEQ ID NOs: 24, 25, and 26, respectively ([0007], [0034-0036], [0265-0270]). Desjarlais teaches a light chain of the TGF-ΒRII binding domain comprising SEQ ID NO: 1315 which is 100% identical to instant SEQ ID NO: 48 and comprises instant CDRs SEQ ID NOs: 49, 50, and 51 ([0007], [0036], [0266-0270]). Regarding claim 38, Desjarlais teaches a host cell comprising a nucleic acid used to produce the heterodimeric antibodies of the invention [0355, 0358].
It would have been obvious for a person of ordinary skill in the art to make a bispecific antibody comprising the anti-PD-1 binding domain comprising SEQ ID NO: 5 and SEQ ID NO: 16 as taught by ‘901 patent et. al. to benefit from the strong anti-PD-1 binding and blocking as taught by ‘901 patent and the common light chain of SEQ ID NO: 24 in an anti-PD-1/anti-TGF-ΒRII bispecific as taught by Desjarlais et. al. and further comprising the anti-TGF-ΒRII binding domain comprising VH SEQ ID NO: 990 and VL SEQ ID NO: 1315 to benefit from making a bispecific with the identical common light chains Desjarlais SEQ ID NO: 1315 and ‘901 patent SEQ ID NO: 24 in order to more efficiently make a bispecific antibody comprising two Fab domains; and further because Desjarlais et. al. teaches that targeting PD-1 and TGF-ΒRII makes an efficacious anti-cancer bispecific antibody. This would have a reasonable expectation of success because methods of making bispecific antibodies with the common light chain were known in the art as taught by Desjarlais et. al.
Copending App. No. 18625756
Claims 16-17, 21-23, 33, and 36-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18625756 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 (PTO-892 dated 3/12/2026).
The ‘756 patent teaches PD-1 binding domains wherein the PD-1 binding domain comprises a HCDRs 1-3 of RX1X2X3X4 wherein one embodiment is RFAL[SNVT], WIX1X2X3X4GX6X7X8X9X10X11X12X13X14 wherein one embodiment is WIDPNTGTPTFAQGVTG, and SEQ ID NO: 68, wherein one embodiment is SLGYCDSDICYPNWIFDN and a VL SEQ ID NO: 16 100% identical to instant SEQ ID NO: 48 and comprising instant CDRs SEQ ID NOs: 49, AAS, and 51. The examiner notes that this embodiment is therefore within the scope of the claims because it is identical to instant SEQ ID NOs: 15, 16, and 17 wherein each HCDR may comprise at most three, two, or one amino acid variations.
The ’756 patent does not teach towards a multispecific binding moiety (MBM) wherein the MBM comprises the anti-PD-1 binding domain of ‘654 and an anti-TGF-ΒRII binding domain; and wherein the anti-TGF-ΒRII binding domain comprises HC SEQ ID NO: 23 or CDRs SEQ ID NOs: 24, 25, and 26.
This deficiency is resolved by Desjarlais et. al. The teachings of Desjarlais et. al. are in the 102 and 103 rejections above. Briefly, Desjarlais et. al. teaches anti-PD-1 and anti-TGF-ΒRII bispecific antibodies that block PD-1 and TGF-ΒRII and further suggests an anti-TGF-ΒRII binding domain SEQ ID NO: 990, which is 100% identical to instant SEQ ID NO: 23 and comprises instant CDRs SEQ ID NOs: 24, 25, and 26, respectively ([0007], [0034-0036], [0265-0270]). Desjarlais teaches a light chain of the TGF-ΒRII binding domain comprising SEQ ID NO: 1315 which is 100% identical to instant SEQ ID NO: 48 and comprises instant CDRs SEQ ID NOs: 49, 50, and 51 ([0007], [0036], [0266-0270]). Regarding claim 38, Desjarlais teaches a host cell comprising a nucleic acid used to produce the heterodimeric antibodies of the invention [0355, 0358].
It would have been obvious for a person of ordinary skill in the art to make a bispecific antibody comprising the anti-PD-1 binding domain comprising SEQ ID NO: 5 and SEQ ID NO: 16 as taught by ‘756 application to benefit from the strong anti-PD-1 binding and blocking as taught by ‘756 and the common light chain of SEQ ID NO: 48 in an anti-PD-1/anti-TGF-ΒRII bispecific as taught by Desjarlais et. al. and further comprising the anti-TGF-ΒRII binding domain comprising VH SEQ ID NO: 990 and VL SEQ ID NO: 1315 to benefit from making a bispecific with the identical common light chains Desjarlais SEQ ID NO: 1315 and ‘756 SEQ ID NO: 48 in order to more efficiently make a bispecific antibody comprising two Fab domains; and further because Desjarlais et. al. teaches that targeting PD-1 and TGF-ΒRII makes an efficacious anti-cancer bispecific antibody. This would have a reasonable expectation of success because methods of making bispecific antibodies with the common light chain were known in the art as taught by Desjarlais et al.
U.S. Patent No. 12570747
Claims 1, 4-7, 10-12, 24-25, 33, and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 12570747 (formerly provisional claims 44-45, 57 90 of copending Application No. 17757953) U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 (PTO-892 dated 3/12/2026) and U.S. Patent No. 11993654 to Plyte et. al. effectively filed 31 March 2021.
The applied reference (U.S. 11993654 to Plyte et. al.) has a common Assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The claims of U.S. Patent No. 12570747 teach an antibody that specifically binds TGF-ΒRII wherein the antibody or antibody VH-CDRs 1-3 of the VHs selected from a list including VH SEQ ID NO: 10 which is 100% identical to instant SEQ ID NO: 23 and comprises instant CDRs SEQ ID NOs: 24, 25, 26 and a light chain having SEQ ID NO: 16 which is 100% identical to instant SEQ ID NO: 48.
‘953 does not teach the TGF-ΒRII binding domain in a multispecific binding moiety further comprising an anti-PD-1 binding domain, wherein the anti-PD-1 binding domain comprises a VH and VL of SEQ ID NO: 18 and 48.
This deficiency is resolved by Desjarlais et. al. and Plyte et. al.
The teachings of Desjarlais et. al. are in the 103 and NSDP rejections above and are incorporated by reference herein.
Plyte et. al. teaches PD-1 binding domains that have a higher affinity for human PD-1 than a reference PD-1 binding domain and having equal or higher potency in blocking ligand binding to PD-1 than a reference antibody, and binding moieties comprising such PD-1 binding domains (Abstract). Plyte et. al. teaches a that the PD-1 binding domain comprises a VH SEQ ID NO: 5 (claims 2 and 3) (100% identical to instant SEQ ID NO: 14 and comprising CDRs instant SEQ ID NOs: 15, 16, and 17) and a VL SEQ ID NO: 16 (claims 5-7) 100% identical to instant SEQ ID NO: 48 and comprising instant CDRs SEQ ID NOs: 49, AAS, and 51). Plyte et. al. teaches that the light chain SEQ ID NO: 16 comprising CDRs 49, AAS, and 51 is a common light chain capable of pairing with multiple different heavy chain which is particularly useful in the generation of bispecific antibodies (Col. 11 lines 24-41). Plyte et. al. teaches that one embodiment of the invention is a multispecific binding moiety comprising at least two binding domains which have specificity for at least two targets or epitopes (Col. 13 line 61- Col. 14 line 5).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make a bispecific antibody comprising the anti-PD-1 binding domain comprising SEQ ID NO: 5 and SEQ ID NO: 16 as taught by Plyte et. al. to benefit from the strong anti-PD-1 binding and blocking as taught by Plyte and the common light chain of SEQ ID NO: 16 in an anti-PD-1/anti-TGF-ΒRII bispecific as taught by ‘953 in view of Desjarlais et. al. and further comprising the anti-TGF-ΒRII binding domain comprising SEQ ID NO: 10 and SEQ ID NO: 16 of ‘953 to benefit from making a bispecific with identical common light chains Desjarlais SEQ ID NO: 1315 (identical to ‘953 SEQ ID NO: 10) and Plyte SEQ ID NO: 16 (identical to ‘953 SEQ ID NO: 16) in order to more efficiently make a bispecific; and further because Desjarlais et. al. teaches that targeting PD-1 and TGF-ΒRII makes an efficacious anti-cancer bispecific antibody. This would have a reasonable expectation of success because methods of making bispecific antibodies with a common light chain were known in the art as taught by Desjarlais et. al. and Plyte et. al.
Regarding claims 13-16, as evidenced by the instant specification Fig. 9F, the antibody of modified Desjarlais et. al. in view of Plyte which has the same sequences as the instant antibody would inherently have the same functions and therefore possess identical functional characteristics.
This NSDP rejection might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Additional provisional NSDP rejections:
Copending Application No.:
Rejected over Application Claims:
SEQ ID NOs identical to instant SEQ ID NOs: 18, 23, and 48 (comprising instant CDRs 15, 16, 17; 24, 25, 26; and 49, 50, 52)
Application/Patent with similar (prov.) NSDP rejections:
18625703
46, 47, 52-73
SEQ ID NO: 6
N/A
SEQ ID NO: 16
U.S. Patent No. 11993654 in view of Desjarlais
19466020
1-40
N/A
SEQ ID NO: 10, 36 (claim 9)
SEQ ID NO: 16 (claim 11)
U.S. Patent No. 12570747 in view of Desjarlais; Plyte
19565712
1-5, 47-51, 54, 56, 57, 59-65, 67-71, 73-75, 78
SEQ ID NO: 4
SEQ ID NO: 9
SEQ ID NO: 14
Copending App. No. 18633748
Response to Arguments
Applicant’s arguments dated 6/12/2026 have been fully considered but are not persuasive. Regarding the NDSP rejections over U.S. Patent No. 11993654 Applicant argues that the NSDP should be withdrawn for the reasons set forth in the arguments of the 103 rejection above. This is not persuasive, as described for the 103 rejection above. Applicant argues that “there was no motivation in the prior art to modify the TGF-BRII x PD-1 antibodies disclosed in Desjarlais because there was no objective reason to combine. Applicant further argues that “even if a skilled person were motivated to replace the PD-1 arm of Desjarlais bispecific antibody, there is no teaching or suggestion that would have led them to select the specific PD-1 binding domain of Plyte. This is not persuasive. MPEP §2144.06 teaches that substituting art-known equivalents for the same purpose is prima facie obvious and an express suggestion to substitute one equivalent for another is not necessary to render the substitution obvious. As described in the 103 rejection above, the anti-PD-1 antibody of Desjarlais and the anti-PD-1 antibody of Plyte were art known-equivalents because both antibodies are PD-1 antibodies for blocking ligand binding to PD-1 and both are disclosed as useful for purpose in the context of a PD-1 blocking bispecific antibody. Even further, as described in the 103 rejection above, there was additional motivation to combine the two antibodies comprising the exact same light chain because both Plyte and Desjarlais teach making bispecific antibodies with common light chains and a person of ordinary skill in the art would understand from the sequences of the anti-PD-1 antibodies of Plyte and the anti-TGFBRII antibodies of Desjarlais that they share a light chain and therefore would be suitable for making a multispecific antibody with a common light chain.
Regarding the NSDP rejection over copending application 18633748, Applicant argues that the method claims are distinct (Remarks p. 12-13). However, Applicant does not explain how the methods claims are patentably distinct. The rejection is maintained for the reasons set forth in the NSDP rejection above because the composition as claimed is made obvious by the claims of application 18633748 in view of Desjarlais as explained above. Applicant further argues that it is a provisional rejection because the claims of that Application have not been granted. The Examiner agrees that the rejection is provisional, but does not agree that the provisional nature of the rejection is reason for withdrawal. If Applicant is referring to the rule that NSDP rejections over later-filed copending Application may be withdrawn if that is the last remaining rejection (MPEP 804.I.B.1.b.iii), the Examiner notes that this is not the last remaining rejection and therefore the provisional rejection stands. Applicant further argues that the arguments raised in the response to 103 section apply. As described for the NSDP of U.S. Patent No. 11993654 and the response to 103 above, these arguments are not persuasive.
Regarding the NSDP over copending Application No. 17708901, Applicant argues that it is a provisional rejection because the claims of that Application have not been granted (Remarks p. 13). The Examiner agrees that the rejection is provisional, but does not agree that the provisional nature of the rejection is reason for withdrawal. If Applicant is referring to the rule that NSDP rejections over later-filed copending Application may be withdrawn if that is the last remaining rejection (MPEP 804.I.B.1.b.iii), the Examiner notes that the effective filing date of 17708901 is 3/31/2021, which is earlier than the instant effective filing date 11/19/2021. Applicant further argues that the arguments raised in the response to 103 section apply(Remarks p. 13). As described for the NSDP of U.S. Patent No. 11993654 and the response to 103 above, these arguments are not persuasive.
Regarding the NSDP over copending Application number 18625756, Applicant argues that it is a provisional rejection because the claims of that Application have not been granted (Remarks p. 14). The Examiner agrees that the rejection is provisional, but does not agree that the provisional nature of the rejection is reason for withdrawal. If Applicant is referring to the rule that NSDP rejections over later-filed copending Application may be withdrawn if that is the last remaining rejection (MPEP 804.I.B.1.b.iii), the Examiner notes that the effective filing date of 18625756 is 3/31/2021, which is earlier than the instant effective filing date 11/19/2021. Applicant further argues that the arguments raised in the response to 103 section apply (Remarks p. 14). As described for the NSDP of U.S. Patent No. 11993654 and the response to 103 above, these arguments are not persuasive.
Regarding the NSDP over copending Application number 17757953, Applicant argues that it is a provisional rejection because the claims of that Application have not been granted (Remarks p. 14). The Examiner agrees that the rejection was provisional, but does not agree that the provisional nature of the rejection is reason for withdrawal. Copending application 17757953 is now U.S. Patent 12570747, and the argument is now moot in view of the new non-provisional rejection, necessitated by amendment, above. Applicant further argues that the arguments raised in the response to 103 section apply. As described for the NSDP of U.S. Patent No. 11993654 and the response to 103 above, these arguments are not persuasive.
Conclusion
No claims are 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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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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