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 .
Election/Restrictions
Applicant’s response to the Restriction/Election requirement dated 20 January 2026 is acknowledged. Upon reconsideration, the Examiner has withdrawn the requirement for restriction between Groups I-XII as described in the Office Action dated 10/17/2025 because of the overlap between the inventions recited in Claims 24-25 and 28-31 which were not included in the original elected Group IV. The Restriction/Election requirement has been replaced with an election of species requirement described below:
Election of Species
This application contains claims directed to the following patentably distinct species:
(i) A single species of complete anti TGF-ΒRII binding comprising a full VH and VL or 3 HCDRs and 3 LCDRs (e.g. the binding domains as recited in claims 24-25)
(ii) A single species of complete anti-PD-1 binding domain as defined by a full VH and VL or 3 HCDRs and 3 LCDRs (e.g. the binding domains as recited in claim 28-30).
Additionally, the election of species (i) and (ii) will be considered to read on a single species of multispecific binding moiety comprising both the anti-TGF-ΒRII and the anti-PD-1 binding domains.
The species are independent or distinct because the species as claimed are directed towards distinct PD-1 or TGF-ΒRII binding domains that are comprised of structurally unrelated polypeptide chains with distinct, mutually exclusive CDRs. For example, below is the multiple alignment of the anti-PD-1 and the anti-TGF-ΒRII heavy chain CDRs, respectively:
Anti-PD-1:
CLUSTAL O(1.2.4) multiple sequence alignment
2 FDFWSYIYYSGSWSLNPSFKGG-------GYTGYGG-DW------FDP 34
3 YHFWSYIVYSGSYNVNPSLKTG-------GYTGYGG-DW------FDP 34
1 -------SYVISMI-IPVFDTSSYEKKFQGGTVEATL--L-----FDF 33
4 -------RFALHWI-DPNTGTPTFAQGVTGSLGYCDSDICYPNWIFDN 40
5 -------RFALSWI-DPNTGTPTYAQDFTGSLGYCGSDICYPNGILDN 40
: * * :*
Anti-TGF-ΒRII:
3 NAWMSRIKTTISGGATDFAAPVKGDLRDY----------- 29
4 NAWMSRIKTTISGGATQFAAPVKGDLRDY----------- 29
1 --IYAMTVISGSGGTTYYADSVKGRGQYRDIVGATDY--- 35
2 --INAMTVISGSGGTTYYADSVKGRGQYRDIVGATDY--- 35
5 --RYAMSAISASGDRTHNTDSVKGGIAAS----GKNYFDP 34
6 --RYAMSAISASGDRTKNTDSVKGGTAAA----GKNYFDP 34
7 --RYAMSAISASGDRTKYTDSVKGGTAAA----GKNYFDP 34
: : **. * : ***
In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, claims 1, 3-7, 10-17, 22, 23, 33, 36-37, and 41 are generic to species election (i) and claims 1, 3-7, 10-15, 24, 25, 31, 33, 36-37, and 41 generic to species election (ii).
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply:
(a) the species or groupings of patentably indistinct species have acquired a separate status in the art in view of their different classifications
(b) the species or groupings of patentably indistinct species have acquired a separate status in the art due to their recognized divergent subject matter
(c) the species or groupings of patentably indistinct species require a different field of search (e.g., searching different classes /subclasses or electronic resources, or employing different search strategies or search queries).
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
During a telephone conversation with Sulay Jhaveri on 5 March 2026 a provisional election was made without traverse to prosecute the species of:
(i) a PD-1 binding domain comprising a heavy chain variable region comprising a CDR1, CDR2, and CDR3 having the amino acid sequences as set forth in SEQ ID NOs 15, 16, and 17, respectively, and comprising a light chain variable domain comprising a CDR1, CDR2, and CDR3 having the amino acids sequences as set forth in SEQs 49, 50, and 51, respectively.
(ii) a TGF-ΒRII binding domain comprising a heavy chain variable region comprising a CDR1, CDR2, and CDR3 having the amino acid sequences as set forth in SEQ ID NOs .
The elected species of multispecific binding moiety is the species comprising both the PD-1 binding domain and the TGF-ΒRII binding domain of elected species (i) and (ii).
The election reads on claims 1, 3-7, 10-17, 20-25, 28-31, 33, 36-41.
Affirmation of this election must be made by applicant in replying to this Office action.
Information Disclosure Statement
The IDSs have been considered except where lined through. The IDS dated 4/17/2023 has not been considered because it is a duplicate of the IDS dated 4/6/2023.
Claim Status
Claims 1, 3-7, 10-17, 20-25, 28-31, 33, 36-41 are pending and under examination in the instant office action.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See p. 18 line 11. The Examiner suggests amending the specification to remove the prefix http://.
Claim Objections
Duplicate claim warning:
Applicant is advised that should claim 20 be found allowable, claim 28 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 36 and 37 are objected to because of the following informalities: the claims recite "an effective amount of a multispecific binding moiety according to claim 1" (emphasis is the Examiner’s). The Examiner requests that the claims be amended to recite “an effective amount of [[a ]]the multispecific binding moiety according to claim 1" in order to make clear the antecedent basis of the dependency. Appropriate correction is required.
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(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4-7, 10-15, 17, 21-23, 30, 37, 39, and 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 contains the trademark/trade name HEK-Blue. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular HEK cell product with genetic modification and reporter assay system and, accordingly, the identification/description is indefinite.
Claim 4-7 and 10-15 are indefinite for recitation of intended result/effect without conferring some structural, material, or manipulative difference on the scope of the claim. Claim 4 recites, “wherein the multispecific binding moiety has a higher potency in blocking TGF-ΒRII-mediated signaling” in PD-1 expressing cells; Claim 5 recites that the cells expressing both PD-1 and TGF- BRII are Jurkat-PD-1+ cells and “in particular wherein the potency in blocking TGF-ΒRII-mediated signaling is measured in a phospho-SMAD2/3 assay”; Claim 6 recites that the cells expressing both PD-1 and TGF- BRII are CD4+ or CD8+ cells and “in particular wherein the potency in blocking TGF-ΒRII-mediated signaling is measured in a phospho-SMAD2/3 assay”; Claim 7 recites that the cells expressing both PD-1 and TGF- BRII are HEK-Blue TGF-B-PD-1+ cells and “in particular wherein the potency in blocking TGF-ΒRII-mediated signaling is measured in an isogenic PD-1-TGF-B reporter assay”; Claim 10 recites “wherein the potency in blocking TGF-βRII-mediated signaling in cells expressing both PD-1 and TGF-βRII is at least about 200 fold”; Claim 11 recites “wherein the potency of the multispecific binding moiety in blocking TGF-βRII mediated signaling in cell expressing TGF-βRII and no PD-1 is lower than the potency of a reference anti- TGF-βRII antibody” and “the potency of the multispecific binding moiety in blocking TGF-βRII mediated signaling in cell expressing TGF-ΒRII and PD-1 is higher than the potency of a reference anti- TGF-βRII antibody” wherein the reference antibody has heavy chain SEQ ID NO: 76 and light chain SEQ ID NO: 77; Claim 12 recites “wherein the potency of the multispecific binding moiety in blocking TGF-ΒRII-mediated signaling in cells expressing both TGF-βRII and PD-1 is at least about 100 fold”; Claim 13 recites “wherein the multispecific binding moiety has a higher activity in reducing tumor volume than a combination of reference antibodies”; Claim 14 recites wherein the activity in reducing tumor volume is determined by measuring tumor volume reduction in an in vivo mouse study, in particular an in vivo mouse study using MDA-MB-231 xenograft huCD34 NSG mice; Claim 15 recites the multispecific antibody wherein a higher activity in reducing tumor volume is a tumor volume reduction of at least about 1.5 fold”. It is unclear whether or not assessing potency in blocking TGF-ΒRII-mediated signaling (in the particular manner or degree required by some of the claims) is required for infringement because methodology is implicit but the claims are directed towards a product rather than a method, and the instant claims and specification are insufficient to describe the metes and bounds of which structures would be expected to meet the functional limitations of the claims. Absent a full description of structures that meet these functions, it is unclear how these claims further limit the scope of the parent claim. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim” (emphasis added). Since the claims fail to meet all (3) criteria set forth in MPEP 2173.05(g), then Claims 4-7 and 10-15 are rejected.
The term “higher potency in blocking” in claims 4, 11, 12; “lower potency in blocking” in claim 11; “higher activity in reducing tumor volume” in claims 13 and 15, are relative terms which render the claims indefinite. The terms higher and activity in reducing tumor volume is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The instant specification teaches that blocking means interfering or modifying the interaction between a ligand and a receptor or causing a total or partial reduction of the signal transduction cascade (p. 5 lines 10-23) and that in some embodiments potency in blocking TGF-βRII mediated signaling is determined in IC50 in a phospho-SMAD2/3 or HEK-BLUE PD-1 TGF-B reporter assay (p. 9 line 20-p. 10 line 11), but this is a non-limiting definition that does not set metes and bounds on the claim. Regarding activity in reducing tumor volume, the specification provides some embodiments but these are also non-limiting (p. 11 lines 7-20). Further, even if the assay and level of blocking was specified or activity in reducing tumor, this still would not be sufficient for a person of ordinary skill in the art to assess the metes and bounds of the claim because the level of potency blocking potency of TGF-βRII signaling is influence by many variables including affinity of the TGFB for the receptor, the cell culture conditions, the expression levels of both PD-1 and TGF-βRII in the cells, and the dosage/concentration of the antibody and the control; these are all limitations that are not fixed; for example, an artisan may use a different promoter than applicant to over-express PD-1 at a different level in Jurkat cells than those Jurkat-PD-1 cells used by the applicant, and the ratio of PD-1 to TGF-βRII expression and the relative saturation of the antibody may all effect the degree of potency in blocking. Because, as described above, there corresponding structures that could be modified by these functional limitations are unclear, it is not possible to ascertain the degree of change required and how that reads onto the genus of instantly claimed structures.
The terms “preferably” in claims 10, 12, 15, 17, 21, 23, 39, 40; “in particular” in claims 5, 6, 7, 14, 37; are exemplary terms which render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant revise the claims to remove the terms “preferably” or “in particular” and the limitations following it.
Regarding claims 22, 30, and 40, the claims recite a “light chain variable region having comprising […] light chain CDR 2 (LCDR2) […] having an amino acid sequence as set forth in […] SEQ ID NO: 50", but SEQ ID NO: 50 is undefined in the sequence listing due to ST.26 format skipping all sequences of less than four amino acids. Therefore claims 22, 30, and 40 fail to delineate the metes and bounds of the subject matter that Applicant regards as the invention with the requisite clarity and particularity to permit the skilled artisan to know or determine the infringing subject matter. Claim amendment to recite the three amino acids (‘AAS’, See Specification p. 94) directly in the claim rather than SEQ ID NO: 50 would circumvent the rejection due to the ST.26 XML format not allowing sequence listings of less than four amino acids.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-7, 10-17, 20-25, 28-31, 33, 36-41 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 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 1, 16, and 24, the claims allow for 1) any binding domain specific to PD-1 and TGF-ΒRII wherein the PD-1 binding domain blocks PD-1 mediated signaling and the TGF-ΒRII domain blocks TGF-βRII mediated signaling but the structures corresponding to binding and blocking of PD-1 and TGF-βRII for were not predictable for any binding domain and 2) 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 1 recites a genus of multispecific binding moieties comprising a PD-1 binding domain and a TGF-ΒRII binding domain, wherein there is no restriction on the structure of the binding domain (e.g. it can be any domain that binds to PD-1 or TGF-βRII such as a peptide (antibody, VHH, coreceptor, antigen), a nucleic acid, or small molecule). 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 24 recites the multispecific binding moiety comprising a PD-1 binding domain and a TGF-βRII 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.
Claim 3 recites wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-βRII, and an Fc region. Claim 41 recites a cell producing a multispecific binding moiety as claimed in claim 1.
Claims 2-7 and 10-12 functional limitations and particular intended effects of the PD-1 and TGF-βRII blocking, but as described in the 112(b) rejection above the metes and bounds are unclear because it is unclear how the functional limitations further limit the claimed structures. Claims 33, 36, 37, and 41 depend from claim 1 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: 1, 5, 9, 13, 14, 18, 19; Claim 20 recites wherein the multispecific binding moiety (MBM) of claim 16 comprises a TGF-ΒRII binding domain defined by particular CDRs (e.g. SEQ ID NOs: 24, 25, and 26) wherein each CDR may comprise up to 3 amino acid variations and the light chains are not defined; Claim 21 recites the a TGF-ΒRII binding domain defined by at least 80% identity to SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88, or 89; 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. Claim 25 recites the TGF-ΒRII domain of the MBM of claim 24 comprises 80% identity to SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88, or 89; Claim 28 recites the MBM of claim 24 wherein the PD-1 binding domain comprises a heavy chain variable region defined by CDRs wherein each CDR may comprise up to 3 amino acid variations; claim 29 recites the MBM wherein the PD-1 binding domain has at least 80% identity to SEQ ID NOs: 1, 5, 9, 13, 14, 18, 19; Claim 30 recites the MBM of claim 28 wherein the PD-1 and/or TGF-βRII binding domain comprises CDRs SEQ ID NOs: 49, 50, and 51 or a variant thereof; claim 31 recites the MBM of claim 28 having a light chain with at least 80% identity to SEQ ID NO: 48.
Claim 38 recites a cell comprising a nucleic acid encoding the heavy chain variable region of a PD-1 binding domain as defined in claim 16 and a nucleic acid sequence encoding a heavy chain variable region of a TGF-ΒRII binding domain, wherein the TGF-βRII binding domain comprises a heavy chain variable region defined by CDRs (e.g. SEQ ID NOs: 24, 25, and 26) wherein each of the HCDRs may comprise at most three amino acid substitutions; claim 39 recites the cells further comprising a nucleic acid sequence encoding a CH1 region; claim 40 recites the cell further comprising at least one nucleic acid sequence encoding the light chain variable region comprising SEQ ID NOs: 49, 50, and 51.
Thus, the scope of the claims is directed to anti-PD-1 and anti- TGF-βRII binding domains wherein the binding domains can be any type of molecule defined only by function; and towards antibody binding domain 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). 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) 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 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) 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. 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 claims 1, 16, and 24 at the time of filing. Regarding claims 3-7, 10-15, 17, 20-23, 25, 28-31, 33, 36-41 the claims are ultimately dependent on the rejected claims 1, 16, and 24 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-7, 10-17, 20-25, 28-31, 33, 36-41 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:
any generic multispecific binding moiety comprising any generic PD-1 binding domain that blocks PD-1 mediated signaling and any generic TGF-ΒRII binding domain that blocks TGF-ΒRII mediated signaling;
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 1 recites a genus of multispecific binding moieties comprising a PD-1 binding domain and a TGF-ΒRII binding domain, wherein there is no restriction on the structure of the binding domain (e.g. it can be any domain that binds to PD-1 or TGFB-RII such as a peptide (antibody, VHH, coreceptor, antigen), a nucleic acid, or small molecule). 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 24 recites the multispecific binding moiety comprising a PD-1 binding domain and a TGF-ΒRII 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.
Claim 3 recites wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-ΒRII, and an Fc region. Claim 41 recites a cell producing a multispecific binding moiety as claimed in claim 1.
Claims 2-7 and 10-12 functional limitations and particular intended effects of the PD-1 and TGF-ΒRII blocking, but as described in the 112(b) rejection above the metes and bounds are unclear because it is unclear how the functional limitations further limit the claimed structures. Claims 33, 36, 37, and 41 depend from claim 1 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: 1, 5, 9, 13, 14, 18, 19; Claim 20 recites wherein the multispecific binding moiety (MBM) of claim 16 comprises a TGF-ΒRII binding domain defined by particular CDRs (e.g. SEQ ID NOs: 24, 25, and 26) wherein each CDR may comprise up to 3 amino acid variations and the light chains are not defined; Claim 21 recites the a TGF-ΒRII binding domain defined by at least 80% identity to SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88, or 89; 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. Claim 25 recites the TGF-ΒRII domain of the MBM of claim 24 comprises 80% identity to SEQ ID NOs: 23, 27, 31, 35, 39, 43, 47, 88, or 89; Claim 28 recites the MBM of claim 24 wherein the PD-1 binding domain comprises a heavy chain variable region defined by CDRs wherein each CDR may comprise up to 3 amino acid variations; claim 29 recites the MBM wherein the PD-1 binding domain has at least 80% identity to SEQ ID NOs: 1, 5, 9, 13, 14, 18, 19; Claim 30 recites the MBM of claim 28 wherein the PD-1 and/or TGF-ΒRII binding domain comprises CDRs SEQ ID NOs: 49, 50, and 51 or a variant thereof; claim 31 recites the MBM of claim 28 having a light chain with at least 80% identity to SEQ ID NO: 48.
Claim 38 recites a cell comprising a nucleic acid encoding the heavy chain variable region of a PD-1 binding domain as defined in claim 16 and a nucleic acid sequence encoding a heavy chain variable region of a TGF-ΒRII binding domain, wherein the TGF-ΒRII binding domain comprises a heavy chain variable region defined by CDRs (e.g. SEQ ID NOs: 24, 25, and 26) wherein each of the HCDRs may comprise at most three amino acid substitutions; claim 39 recites the cells further comprising a nucleic acid sequence encoding a CH1 region; claim 40 recites the cell further comprising at least one nucleic acid sequence encoding the light chain variable region comprising SEQ ID NOs: 49, 50, and 51.
Thus, the scope of the claims is directed to anti-PD-1 and anti-TGF-ΒRII binding domains wherein the binding domains can be any type of molecule defined only by function; and towards antibody binding domain 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). 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) 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 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) 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. 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 any PD-1 and any TGF-ΒRII binding domain (not limited to antibody binding domains) possesses the claimed functions of blocking PD-1 and blocking TGF-ΒRII, 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.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-7, 10-12, 33, 36-37, and 41 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020.
Regarding claim 1, 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].
Regarding claims 4, 6, 10, 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.
Regarding claims 5 and 7, as explained in the 112(b) rejection above, it is indefinite how the functional limitations limit the structure of the anti-PD-1/anti-TGF-ΒRII MBM as recited in claim 1. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. For the purposes of expedited prosecution, based on the blocking experiments of Desjarlais et. al. Fig. 57 and [0389], the structure of the bispecific of Desjarlais et. al. possessing the anti-PD-1 and anti-TGF-ΒRII blocking domains would naturally meet the functional limitations of higher potency in blocking Jurkat-PD-1+ and HEK-Blue-TGFB-PD-1+ cells expressing TGF-ΒRII than in Jurkat-PD-1- cells and HEK-Blue-TGFB-PD-1- expressing TGF-ΒRII, respectively.
Regarding claims 11-12, as explained in the 112(b) rejection above, it is indefinite how the functional limitations limit the structure of the anti-PD-1/anti-TGF-ΒRII MBM as recited in claim 1. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. For the purposes of expedited prosecution, 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].
For the purposes of expedited prosecution, based on the blocking experiments of Desjarlais et. al. Fig. 29 and 30 and [0382], the structure of the bispecific of Desjarlais et. al. possessing the anti-PD-1 and anti-TGF-ΒRII blocking domains would naturally meet the functional limitations of higher blocking of TGF-ΒRII compared to a reference anti-TGF-ΒRII bivalent monospecific comprising SEQ ID NO: 76 and 77 as described.
Regarding claim 33, Desjarlais discloses pharmaceutical compositions comprising the antibodies and pharmaceutically acceptable carriers [0359].
Regarding claim 36 and 37, 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). Regarding claim 41, 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).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020.
Regarding claims 24 and 25, 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 teaches a list of potential TGF-ΒRII binding domain heavy chain and light chain sequences 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]).
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over 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 teachings of Desjarlais et. al. in regards to claim 1 are in the 102 rejection above and are incorporated by reference herein.
Regarding claim 3, Desjarlais et. al. teaches that the bispecific antibody may be in multiple formats including formats wherein there are 2 Fab domains and the bispecific is generated by interaction of heterodimeric Fc domains (Fig. 14-15). Desjarlais et. al. teaches that in cases where there are two Fab domains the antibody can use a common light chain ([0331]; [0342]). As described above, Desjarlais et. al. teaches the light chain of the TGF-ΒRII domain comprising SEQ ID NO: 1315. Desjarlais et. al. teaches “Accordingly, in some embodiments the present invention provides heterodimeric immunomodulatory antibodies that rely on the use of two different heavy chain variant Fc sequences, that will self-assemble to form heterodimeric Fc domains and heterodimeric antibodies […] An ongoing problem in antibody technologies is the desire for “bispecific” antibodies that bind to two different antigens simultaneously, in general thus allowing the different antigens to be brought into proximity and resulting in new functionalities and new therapies. In general, these antibodies are made by including genes for each heavy and light chain into the host cells. This generally results in the formation of the desired heterodimer (A-B), as well as the two homodimers (A-A and B-B (not including the light chain heterodimeric issues)). However, a major obstacle in the formation of bispecific antibodies is the difficulty in purifying the heterodimeric antibodies away from the homodimeric antibodies and/or biasing the formation of the heterodimer over the formation of the homodimers” [0205-0206]. Desjarlais teaches “Interestingly in comparing the activity of XENP34287 and XENP34288 with XENP33045, it appears that using a Fab domain for PD-1 targeting enhances the potency of the anti-TGFßRII×anti-PD1 bsAbs” [0383].
Desjarlais et. al. does not teach the multispecific binding moiety wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab that binds to TGF-ΒRII, and an Fc region.
This deficiency is resolved by Brinkmann et. al.
Brinkmann et. al. teaches that bispecific antibodies come in a large variety of formats, in particular Fc-modified IgGs, a category which contains a large number of formats comprising a single Fab binding to a first antigen and a single Fab binding to a second antigen with an Fc domain (see for example, IgG(kih) and IgG(kih) common light chain, Fig. 2 category 7). In the “Bispecific IgGs with asymmetric architecture” section Brinkmann, like Desjarlais, teaches various methods of generating a bispecific antibody with two different heavy and light chain (¶2, 4) with methods such as preferential dimerization or with a two different heavy chains and a common light chain (¶12, 14, 21).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create a bispecific in a format comprising two Fabs and an Fc domain as taught by Brinkmann et. al. comprising an anti-PD-1 Fab and an anti-TGF-ΒRII Fab as taught by Desjarlais et. al. for targeting anti-PD-1 and anti-TGF-ΒRII for cytotoxic tumor activity and with an anti-PD-1 Fab domain for enhanced potency as taught by Desjarlais. This would have a reasonable expectation of success because methods of making bispecific antibodies in particular formats were well-described and taught by both Brinkmann et. al. and Desjarlais et. al., and an artisan reading the preferred formats of Desjarlais would have a reasonable expectation that they could make and use a bispecific antibody using the domains of Desjarlais et. al. in an alternate format, such a substituting a Fab domain for the scFv in the 1+1 Fab-scFv-Fc format (Fig. 14 A) with a reasonable expectation that the particular VH and VL combinations as taught by Desjarlais et. al. would maintain their binding and blocking functions to the PD-1 and TGF-ΒRII targets.
Claims 13-16, 17, 20-23, 28-31, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020 as applied to claims 1 and 24 above in view of U.S. 11993654 to Plyte et. al. effectively filed 31 March 2021.
The applied reference 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 teachings of Desjarlais et. al. in regards to claims 1 and 24 are in the 102 and 103 rejections above and are incorporated by reference herein.
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 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 rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 11993654
Claims 1, 4-7, 10-17, 20-25, 28-31, 33, 36-41 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.
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 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]).
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 a common light chain were known in the art as taught by Desjarlais et. al.
Claim 3 is 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, 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 teachings of claims 1-20 of the ‘654 patent in view of Desjarlais as applied to claim 1 are in the non-statutory double patenting (NSDP) rejection above.
The ‘654 claims in view of Desjarlais do not teach wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-ΒRII, and an Fc region.
This deficiency is resolved by Brinkmann.
Brinkmann et. al. teaches that bispecific antibodies come in a large variety of formats, in particular Fc-modified IgGs, a category which contains a large number of formats comprising a single Fab binding to a first antigen and a single Fab binding to a second antigen with an Fc domain (see for example, IgG(kih) and IgG(kih) common light chain, Fig. 2 category 7). In the “Bispecific IgGs with asymmetric architecture” section Brinkmann, like Desjarlais, teaches various methods of generating a bispecific antibody with two different heavy and light chain (¶2, 4) with methods such as preferential dimerization or with a two different heavy chains and a common light chain (¶12, 14, 21).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create a bispecific in a format comprising two Fabs and an Fc domain as taught by Brinkmann et. al. comprising an anti-PD-1 Fab and an anti-TGF-ΒRII Fab as taught by the ‘654 claims in view of Desjarlais et. al. for targeting anti-PD-1 and anti-TGF-ΒRII for cytotoxic tumor activity and the light chain in common between the ‘654 claims and the light chain as taught by Desjarlais et. al. This would have a reasonable expectation of success because methods of making bispecific antibodies in particular formats were well-described and taught by both Brinkmann et. al. and Desjarlais et. al., and an artisan reading the preferred formats of Desjarlais would have a reasonable expectation that they could make and use a bispecific antibody with common light chains as taught by Desjarlais comprising the identical light chain in an anti-PD-1 domain as taught by ‘654 claims and with the common light chain used for Fabs binding two different target antigens as taught by Brinkmann.
Copending App. No. 18633748
Claims 1, 4-7, 10-17, 22-23, 33, 36-37, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-55 of copending Application No. 18633748 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '748 application anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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. Thus, although the claims are not identical, they are not patentably distinct because a method comprising a composition anticipates the composition as claimed.
Claim 3 is provisionally rejected 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.
The teachings of claims 1-55 of copending application no. 18633748 as applied to claim 1 above are in the NSDP rejection above and are incorporated herein.
The ‘654 claims in view of Desjarlais do not teach explicitly wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-ΒRII, and an Fc region.
This deficiency is resolved by Brinkmann.
Brinkmann et. al. teaches that bispecific antibodies come in a large variety of formats, in particular Fc-modified IgGs, a category which contains a large number of formats comprising a single Fab binding to a first antigen and a single Fab binding to a second antigen with an Fc domain (see for example, IgG(kih) and IgG(kih) common light chain, Fig. 2 category 7). In the “Bispecific IgGs with asymmetric architecture” section Brinkmann, like Desjarlais, teaches various methods of generating a bispecific antibody with two different heavy and light chain (¶2, 4) with methods such as preferential dimerization or with a two different heavy chains and a common light chain (¶12, 14, 21).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create a bispecific in a format comprising two Fabs and an Fc domain as taught by Brinkmann et. al. comprising an anti-PD-1 Fab and an anti-TGF-ΒRII Fab as taught by the ‘748 claims in view of Desjarlais et. al. for targeting anti-PD-1 and anti-TGF-ΒRII for cytotoxic tumor activity and the light chain in common between the two binding domains of the ‘748 application and comprising an Fc domain. This would have a reasonable expectation of success because methods of making bispecific antibodies in particular formats were well-described and taught by both Brinkmann et. al. and an artisan reading the preferred formats of the ‘748 would have a reasonable expectation that they could make and use a bispecific antibody with an Fc domain and two Fabs with common light chains as taught by Brinkmann comprising the identical light chain in an anti-PD-1 domain as taught by ‘748 claims.
Claims 20-21, 24-25, 28-31, 38, 39, and 40 are provisionally rejected 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.
This is a provisional nonstatutory double patenting rejection.
The teachings of the claims of ‘784 application are in the non-statutory double patenting (NSDP) rejection above and are incorporated by reference herein.
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 102 and 103 rejections 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]).
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 1, 4-7, 10-17, 20-25, 28-31, 33, 36-41 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.
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 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]).
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 a common light chain were known in the art as taught by Desjarlais et. al.
Claim 3 is provisionally 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, 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 teachings of claims 1-20 of the ‘901 patent in view of Desjarlais as applied to claim 1 are in the non-statutory double patenting (NSDP) rejection above.
The ‘901 claims in view of Desjarlais do not teach wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-ΒRII, and an Fc region.
This deficiency is resolved by Brinkmann.
Brinkmann et. al. teaches that bispecific antibodies come in a large variety of formats, in particular Fc-modified IgGs, a category which contains a large number of formats comprising a single Fab binding to a first antigen and a single Fab binding to a second antigen with an Fc domain (see for example, IgG(kih) and IgG(kih) common light chain, Fig. 2 category 7). In the “Bispecific IgGs with asymmetric architecture” section Brinkmann, like Desjarlais, teaches various methods of generating a bispecific antibody with two different heavy and light chain (¶2, 4) with methods such as preferential dimerization or with a two different heavy chains and a common light chain (¶12, 14, 21).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create a bispecific in a format comprising two Fabs and an Fc domain as taught by Brinkmann et. al. comprising an anti-PD-1 Fab and an anti-TGF-ΒRII Fab as taught by the ‘901 claims in view of Desjarlais et. al. for targeting anti-PD-1 and anti-TGF-ΒRII for cytotoxic tumor activity and the light chain in common between the ‘901 claims and the light chain as taught by Desjarlais et. al. This would have a reasonable expectation of success because methods of making bispecific antibodies in particular formats were well-described and taught by both Brinkmann et. al. and Desjarlais et. al., and an artisan reading the preferred formats of Desjarlais would have a reasonable expectation that they could make and use a bispecific antibody with common light chains as taught by Desjarlais comprising the identical light chain in an anti-PD-1 domain as taught by ‘901 claims and with the common light chain used for Fabs binding two different target antigens as taught by Brinkmann.
Copending App. No. 18625756
Claims 1, 4-7, 10-17, 20-25, 28-31, 33, 36-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of U.S. Patent No. 11993654 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.
The applied reference 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 ‘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 although the claims do not recite an embodiment with the exact CDRs currently, the application teaches SEQ ID NO: 5 which is identical to instant SEQ ID NO: 14.
The ‘756 patent does not explicitly teach an anti-PD-1 binding domain comprising a VH of instant SEQ ID NO: 14 and comprising instant CDRs 15, 16, and 17.
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).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the amino acid H in the X4 position of HCDR1 of ‘756 as taught by Plyte et. al. in order to benefit from an alternate embodiment of anti-PD-1 CDRs of nearly identical anti-PD-1 antibodies as taught by ‘756 and Plyte. This would have a predictable effect because ‘756 teaches that residue X4 may be substituted and maintain binding to PD-1 and Plyte et. al. teaches that the particular embodiment with X4 = H binds strongly to PD-1.
The ’756 patent is 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]).
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 a common light chain were known in the art as taught by Desjarlais et. al.
Claim 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 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
The teachings of claims 1-20 of the ‘654 patent in view of Desjarlais as applied to claim 1 are in the non-statutory double patenting (NSDP) rejection above.
The ‘654 claims in view of Desjarlais do not teach wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-ΒRII, and an Fc region.
This deficiency is resolved by Brinkmann.
Brinkmann et. al. teaches that bispecific antibodies come in a large variety of formats, in particular Fc-modified IgGs, a category which contains a large number of formats comprising a single Fab binding to a first antigen and a single Fab binding to a second antigen with an Fc domain (see for example, IgG(kih) and IgG(kih) common light chain, Fig. 2 category 7). In the “Bispecific IgGs with asymmetric architecture” section Brinkmann, like Desjarlais, teaches various methods of generating a bispecific antibody with two different heavy and light chain (¶2, 4) with methods such as preferential dimerization or with a two different heavy chains and a common light chain (¶12, 14, 21).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create a bispecific in a format comprising two Fabs and an Fc domain as taught by Brinkmann et. al. comprising an anti-PD-1 Fab and an anti-TGF-ΒRII Fab as taught by the ‘654 claims in view of Desjarlais et. al. for targeting anti-PD-1 and anti-TGF-ΒRII for cytotoxic tumor activity and the light chain in common between the ‘654 claims and the light chain as taught by Desjarlais et. al. This would have a reasonable expectation of success because methods of making bispecific antibodies in particular formats were well-described and taught by both Brinkmann et. al. and Desjarlais et. al., and an artisan reading the preferred formats of Desjarlais would have a reasonable expectation that they could make and use a bispecific antibody with common light chains as taught by Desjarlais comprising the identical light chain in an anti-PD-1 domain as taught by ‘654 claims and with the common light chain used for Fabs binding two different target antigens as taught by Brinkmann.
Copending App. No. 17757953
Claims 1, 4-7, 10-12, 24-25, 33, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 44-45, 57 90 of U.S. Patent No. 17757953 in view of U.S. 20220144956 to Desjarlais et. al. effectively filed 6 November 2020.
The Examiner notes that copending application 17757953 is schedule to be issued as U.S. Patent No. 125570747 on 3/10/2026, but as it has not issued as of the writing of this office action the rejection is provisional.
The claims of U.S. Patent No. 17757953 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.
This deficiency is resolved by Desjarlais et. al.
The teachings of Desjarlais et. al. are in the 102, 103, and NSDP rejections above and are incorporated by reference herein.
It would have been obvious for a person of ordinary skill in the art to use the anti-TGF-ΒRII antibody comprising SEQ ID NO: 10 and SEQ ID NO: 16 of the ‘953 claims in the anti-TGF-ΒRII/anti-PD1 multispecific binding moiety in order to benefit from a particular embodiment of the effective anti-TGF-ΒRII binding domains as taught by Desjarlais and because SEQ ID NO: 10 of ‘953 claims is 100% identical to SEQ ID NO: 990 of Desjarlais. This would have a reasonable expectation of success because Desjarlais et. al. teaches the binding domain VH of SEQ ID NO: 990 (100% identical to SEQ ID NO: 10 of the ‘953 claims) and therefore an artisan would expect that this particular anti-TGF-ΒRII domain with a common light chain of ‘953 SEQ ID NO: 16 would work in the bispecific antibody of Desjarlais et. al.
Claim 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 57 of U.S. Patent 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 teachings of claims 57of the ‘953 application in view of Desjarlais as applied to claim 1 are in the non-statutory double patenting (NSDP) rejection above.
The ‘953 claims in view of Desjarlais do not teach wherein the multispecific binding moiety comprises a single Fab domain that binds to PD-1, a single Fab domain that binds to TGF-ΒRII, and an Fc region.
This deficiency is resolved by Brinkmann.
Brinkmann et. al. teaches that bispecific antibodies come in a large variety of formats, in particular Fc-modified IgGs, a category which contains a large number of formats comprising a single Fab binding to a first antigen and a single Fab binding to a second antigen with an Fc domain (see for example, IgG(kih) and IgG(kih) common light chain, Fig. 2 category 7). In the “Bispecific IgGs with asymmetric architecture” section Brinkmann, like Desjarlais, teaches various methods of generating a bispecific antibody with two different heavy and light chain (¶2, 4) with methods such as preferential dimerization or with a two different heavy chains and a common light chain (¶12, 14, 21).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create a bispecific in a format comprising two Fabs and an Fc domain as taught by Brinkmann et. al. comprising an anti-PD-1 Fab and an anti-TGF-ΒRII Fab as taught by the ‘753 claims in view of Desjarlais et. al. for targeting anti-PD-1 and anti-TGF-ΒRII for cytotoxic tumor activity and the light chain in common between the ‘753 claims and the light chain as taught by Desjarlais et. al. This would have a reasonable expectation of success because methods of making bispecific antibodies in particular formats were well-described and taught by both Brinkmann et. al. and Desjarlais et. al., and an artisan reading the preferred formats of Desjarlais would have a reasonable expectation that they could make and use a bispecific antibody with common light chains as taught by Desjarlais comprising the identical light chain in an anti-PD-1 domain as taught by ‘753 claims and with the common light chain used for Fabs binding two different target antigens as taught by Brinkmann.
Claims 13-16, 17, 20-23, 28-31, and 38-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 57 of U.S. Patent 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 U.S. 11993654 to Plyte et. al. effectively filed 31 March 2021.
The applied reference 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).
‘953 in view of Desjarlais does not teach the 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).
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: 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
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678