DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendment filed 21 November 2025 is acknowledged. Claims 3-8 are canceled. Claims 1, 9, 21, 23, 35, and 36 are amended. New claim 40 is added.
Claim Status
Claims 1, 9, 19-24, 34-37, and 39-40 are pending. Claims 20, 22, 34, and 36 are withdrawn from consideration, there being no allowable linking or generic claim as described in the Non-final Office Action dated 22 May 2025 p. 2-3. Claims 1, 9, 19, 21, 23, 24, 35, 37, and 39-40 are under examination in the instant office action.
Information Disclosure Statement- New
The IDS dated 11/21/2025 has been considered except where lined through. Regarding the 6th foreign reference WO2021032951 to Gammadelta Therapeutics, the Examiner notes that the applicant appears to have made an inadvertent typographical error. The corresponding uploaded document is WO2021032961 to Gammadelta Therapeutics. WO2021032951 A1 is assigned to Bae Systems PLC and does not appear to be related; therefore, only WO2021032961 to Gammadelta Therapeutics has been considered as marked on the IDS annotations.
Withdrawal of Rejections
The rejection of claims 1, 4, 7, 9, 19, 23, 24, 37 and 39 on the basis that it contains an improper Markush grouping of alternatives is withdrawn in view of the amendment to the claims.
Specification- Maintained
The disclosure is objected to because of the following informalities: The brief description of Figure 20 p. 6 line 8 reads “modifiedanti-Vδ1” which appears to inadvertently lack a space. The examiner believes it should read “modified anti-Vδ1”.
Appropriate correction is required.
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. The examiner recommends deleting the prefix “http://” on p. 40 line 11.
The use of the term G-REX® (p. 139 line 18, p. 156 line 5, p. 157 line 8), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Response to Arguments
Applicant argues that they have submitted a clean and marked up substitute specification to obviate the objections above. However, no such specifications were submitted with the amendment filed 21 November 2025. Therefore, the objections are maintained.
Claim Interpretation- New, necessitated by amendment
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Regarding claims 1 and 23, the claims recite antibody or fragment thereof means for binding to delta variable 1 (Vδ1). Although the general structure of an “antibody or fragment thereof” is known in the art, this is a generic placeholder in the absence of defined CDRs because the recited structure on its own is insufficient to define the structure that performs the binding. Thus, although the antibody or fragment thereof limits the structural backbone to an antibody or antibody fragment (i.e. a peptide comprising a VH and VL or 6 CDRs in an immunoglobulin framework), there is no structure that performs the recited function in the absence of particular VH/VL or CDR sequences. The “means” is followed by the functional language of “binding delta variable 1”, which meets the functional language required in the test prong (B). Lastly, the means is not modified by sufficient structure or material for performing the claimed function. Thus, the broadest reasonable interpretation of “means for binding delta variable 1” is limited by the description in the specification.
The specification discloses isolated anti-Vδ1 antibodies or fragments thereof, wherein a CDR3 comprises a sequence having at least 80% identity with any one of SEQ ID NOs: 2-25; a CDR2 comprising a sequence having at least 80% identity with any one of SEQ ID NOs: 26-37 and sequences A1-A12; and/or a CDR1 comprising a sequence having at least 80% identity with any one of SEQ ID NOs: 38-61 (See specification p. 19 lines 5-15 in particular, and the entirety of p. 19-). The broadest reasonable interpretation of the claim, therefore, the instant claim is directed towards all of the antibody CDR sequence as disclosed in the specification to perform the function of binding to delta variable 1 as well as any art-known equivalents (antibodies or antibody fragments) that perform the function of binding to delta variable 1 (MPEP 2181).
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
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.
Claim 40 is 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 40 is rejected for the reference to “a heavy chain CDR1, CDR2, CDR3 sequence and a light chain CDR1, CDR2, CDR3 sequence of an entire single row of Table 3” (lines 2-3). As stated in MPEP §2173.05(s), “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim.” The examiner suggests listing the CDR SEQ ID NOs of the species listed in Table 3 (e.g. “a) comprising heavy chain CDRs 1-3 of SEQ ID NOs: 38, 26, and 2, respectively and light chain CDRs 1-3 of SEQ ID NOs: 50, VAS, and 14, respectively”).
Claim Rejections - 35 USC § 112(a)- Maintained, changes necessitated by amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9, 19, 23, 24, 37 and 39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) 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.
Claims 1 and 23 allow for changes to the CDR within the VH and VL 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 a vδ-1.
Scope of the claimed genus
As described in the claim interpretation section above, amended claims 1 and 23 invoke 112(f) by reciting a means for binding delta variable 1. The instant specification recites means for binding delta variable 1 described by a genus of antibodies with at least 80% identity to one or more CDRs identified by particular SEQ ID NOs as described. MPEP 2181.II.C.IV states:
The Federal Circuit has recognized the problem of providing a sufficient disclosure for functional claiming, particularly with generic claim language, explaining that "The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the applicant [inventor] has made a generic invention that achieves the claimed result and do so by showing that the applicant [inventor] has invented species sufficient to support a claim to the functionally-defined genus." Ariad Pharmaceuticals Inc. v. Eli & Lilly Co., 598 F.3d 1336, 1349, 94 USPQ2d 1161, 1171 (Fed. Cir. 2010) (en banc).
Thus, the means- (or step-) plus- function claim must still be analyzed to determine whether there exists corresponding adequate support for such claim limitation under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. In considering whether there is 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph support for the claim limitation, the examiner must consider whether the specification describes the claimed invention in sufficient detail to establish that the inventor or joint inventor(s) had possession of the claimed invention as of the application's filing date. Additionally, any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claim as to enable one skilled in the pertinent art to make and use the claimed invention.
Claims 1 and 23 thus do not fully identify the CDRs of the light and heavy chain, allowing mix and match between light and heavy chain CDRs and with the sequences claimed by percent identity only. In fact, as written, the means plus function language encompasses the 80% identity to only one CDR language as well as any and all art-known equivalents that perform the function of binding to Vδ1. Additionally, claim 23 as written recites and/or between the 3 CDRs, and therefore requires only 1 CDR of the required sequences. These claims would therefor encompass an unknown number of additional antibodies with unknown structure. Dependent claims 9, 19, 24, 37 and 39 do limit the CDRs beyond what is claimed in independent claims 1 and 23.
To form a functional antibody, a distinct combination of 6 CDRs is needed.
Claims 21 and 35 recite particular antigen-binding region structures that bind to delta variable 1, and therefore are not interpreted under 112(f) as described above.
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 (Of record, PTO-892 dated 5/22/2025, 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, of record IDS dated 8/7/2024) 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” 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 does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
In regards to anti-Vδ1 antibodies, other anti-Vδ1 antigen binding sites are known in the art. For example, WO2019147735 to Koide et. al. (Of Record, cited in IDS dated 9/2/2022) teaches 17 anti-TCR delta variable 1 antibodies (Table 1). Koide does not teach the specific sequences of the epitopes for their antibodies; it would then be unknown if they fall into or met all the limitations of the claimed antibodies.
Summary of Species disclosed in the original specification
The instant specification discloses 12 species of anti-Vδ1 antibodies, each comprising 3 light chain and 3 heavy chain CDRs (Spec. Table 3, p. 145). Of these, clones G04 E04, F07, and G09 share at least 80% identity to HCDR1 and HCDR2 of elected species SEQ ID NOs: 40 and 28; only clone G04 has 80% identity to HCDR3 of elected species SEQ ID NO: 4; only clone G04 has 80% identity to LCDR1 of elected species SEQ ID NO: 52; clones G04, C05, E04, F07, G09, B09 share LCDR2 of elected species DAS; and only clone G04 has 80% identity to LCDR3 of elected species of SEQ ID NO: 16. Therefore, there is only 1 antibody example of the instant elected species.
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants to allow substitution, addition, or deletion of any amino acid and mix and match heavy and light chain CDRs of 80% identity to CDR3 of SEQ ID NOs: 2-25, CDR2 of SEQ ID NOs: 26-37, VAS, YDS, DAS, AAS, and EVS, and CDR1 of SEQ ID NOs: 38-61.
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 applicant identifies 12 antibody clones capable of binding T cell receptor of gamma delta T cells (Table 3) within the scope of the instant claims, and only 1 species within the scope of the instant species election.
Given the variability encompassed by the genus of anti-TCR delta variable 1 antibodies described species therefore cannot be considered representative of the genus. 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 coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
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 coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the 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 binding activity.
As noted above, the art identifies a number of species of anti-TCR delta variable 1 antibodies but does not characterize all of the functions of those binding moieties. It is unclear if the antibodies of Koide would meet all the requirements of the claims. Koide teaches their binding to delta variable 1 but does not teach the specific sequences of the epitopes for their antibodies.
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 coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the 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 binding activity.
Although the specification describes 12 alternate antibodies, some with sequence similarity to the instant claimed antibodies and maps the target epitopes of the antibodies (See Figs. 7-11; this would be insufficient to describe a structure/function relationship between the antibody paratope/epitope because even the non-contacting residues of an antibody. 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. PMID: 30386328; PMCID: PMC6198058 teaches: "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”. Thus, as described above by Chiu et. al. and Dondelinger et. al., an artisan would not have understood that the instant specification describes a structure/function relationship that supports possession of a genus.
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 Vδ1. 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 antibody of claims 1 and 23 at the time of filing. Regarding claims 4, 7, 9, 19, 21, 24, 35, 37 and 39 the claims are ultimately dependent on the rejected claims 1 and 23 without sufficiently narrowing the claimed subject matter and thus are also rejected.
Claims 1, 9, 19, 23, 24, 37 and 39 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 a composition and method of treatment comprising the antibody CDRs of 3 heavy chain and 3 light chain CDRs of the 12 antibodies of specification Table 3, does not reasonably provide enablement for any antibody with mix-and-match light and heavy chain CDRs of the sequences (claims 1 and 23) comprising at least 80% identity to the instant CDRs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use 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.
Guidance/Working Examples
The application discloses 12 working combinations of 6 CDRs that produce an antibody that binds TCR delta variable 1 (Table 3). All 12 antibodies showed binding activity (Example 5 and 6).
Breadth of Claims
The claims are directed to an antibody comprising different CDR sequences that binds TCR delta variable 1 and method of treating cancer, an infectious disease, or an inflammatory disease comprising the antibody as described in the Claim Interpretation section and the written description rejection above.
As described in the Claim Interpretation Claims 1 and 23 do not fully define the CDRs with percent identity only and with mix-and-match allowed between the light and heavy chain CDRs. This claim would encompass many antibodies with unknown structure and unknown binding.
Claims 9, 19, 24, 37 and 39 do not further limit the CDR sequences and are as broad as the antibody as claims 1 or 23.
Claims 4 and 7 recite CDRs with 100% identity, but restrict only the heavy or only the light chain, respectively.
Claims 21 and 35 recite at least 80% identity to SEQ ID NO: 112, which adds some structure to the positions of the 6 CDRs, but still allows for changes in the CDR residues and does not require the complete structure of 6 CDRs.
To form a functional antibody a distinct combination of 6 sequences is needed. The instant claims 31 are to a large number of antibodies with unknown binding for the target antigen.
State of the Art/Predictability
The claims are directed to antibodies that bind TCR delta variable 1 (Table 3) and methods of treatment using the antibodies. Gamma delta T cells are a subset of T cells that express a distinct surface marker. The TCR on these cells are made up of one gamma and one delta chain with a lower number of V genes when compared to other T cells (Specification page 1 in lines 28-31).
The modulation of gamma delta T cells is known for use in cancer treatment. Antibodies that bind human gamma delta T cells are know that in the art for this therapeutic use (Koide (WO 2019/147735 A1) (IDS dated 9/2/2022) (Abstract and page 2 in lines 10-16 and Example 4). Koide teaches 17 anti-TCR delta variable 1 antibodies (Table 1).
As described in the written description rejection above, it has been established for decades 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 (Of record, PTO-892 dated 5/22/2025) (see Section “The IgG Molecule” in paragraph 1 and Figure 1). The instant application describes the bispecific antibodies having at least a VH and VL each comprising 3 CDRs (p. 9 lines 9-11), but the breadth of instant claim 1 could contain more or only 3 (one chain of CDRs 1-3 could match the instant claims) given the different confirmations described. 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). Further, the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function, as evidenced by Rudikoff et al., Proc. Nat’l Acad. Sci. USA, 79:1979-83 (1982). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Of record, PTO-892 dated 5/22/2025). E.g., Abstract. Similarly, Brown et al., J. Immunol., 156(9):3285-91 (1996) (Of record, PTO-892 dated 5/22/2025), teaches that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. (Brown, p. 3290 and Tables 1 and 2). Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. Accordingly, the skilled artisan recognized that it was highly unpredictable that any of the CDRs could be modified without altering or abolishing antigen binding.
The earlier work of Rudikoff and Brown is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (Of record, IDS dated as described in the written description rejection above (cited in IDS 8/7/2024). Chiu teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3 In the decades since Rudikoff the field has increased understanding of antibody engineering. Structure-Based antibody engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in Section 2 in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but notes it is still not possible to predict the point mutations that would improve affinity in both antibodies and multispecific molecules (Page 51 in lines 6-12).
The specification shows 12 combinations of CDRs that would assemble between the variable heavy and variable light chains and bind TCR delta variable 1. The specification does not show this for the unknown number of CDR combinations of the instant claims. The specification does not show that the many possible variations of in the CDRs would retain binding to TCR delta variable 1.
Conclusion
Taken together, the instant claimed antibodies comprising a large variability of CDR sequences and domain arrangements are not enabled. It would require undue experimentation to obtain and use anti-TCR delta variable 1 antibodies comprising with proper pairing of the recited CDR sequences in functional arrangements to form a functional binding protein, and to use these in a method of treating as claimed.
The specification does not enable any person skilled in the art to which it pertains, or which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Response to Arguments
Applicant argues that the amendments to claims 1, 21, 23, 35, and 36 render the rejection moot. However, as described in the 112(a) rejection and the Claim Interpretation section above, the scope of the amended claims encompasses antibodies with 80% identity or less than 6 complete CDRs disclosed by the specification. In fact, the scope of the claims now includes any equivalents thereof that perform the “means for binding variable delta 1”. As described above, an artisan would not believe the Applicant to have been in possession of all the products and methods disclosed in the specification and equivalents and would not be enabled to make and use all of the antibodies and methods of treatment encompassed by the broadened claims.
Claim Rejections - 35 USC § 102- New, necessitated by amendment
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.
Claim(s) 1, 9, 19, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2019147735 to Koide et. al. published 1 August 2019 (Of record, IDS dated 9/2/2022).
Claim interpretation: As described in the claim interpretation section above, claims 1 and 23 meet the requirements of the 3-prong test in order to be interpreted under 112(f). Claims 9, 19, 24, 37, and 39 depend from claims 1 and 23 and do not further recite sufficient structure performing the means for binding in order to perform the recited function, and therefore are also interpreted by the BRI as referring to those means disclosed in the specification, described in the Claim Interpretation section above, and equivalents. Claims 21 and 35 recited SEQ ID NO: 112, which comprises sufficient structure to perform the recited function of binding Vδ1, and therefore are not interpreted under 112(f). The broadest reasonable interpretation of the claim, therefore, the instant claim is directed towards all of the antibody CDR sequence as disclosed in the specification to perform the function of binding to delta variable 1 as well as any art-known equivalents (antibodies or antibody fragments) that perform the function of binding to delta variable 1 (MPEP 2181).
Koide et. al. teaches “antibodies specific to a delta1 chain of a γδ T cell receptor and methods of using such for modulating γδ T cell bioactivity” (Abstract) (reads on means for binding delta variable 1 as described in the claim interpretation section above). The antibodies comprise 3 heavy chain CDRs and 3 light chains CDRs (e.g. p. 27 line 13-p. 32).
Regarding claim 1, Koide et. al. teaches a method of treating cancer comprising administering a pharmaceutical composition comprising the antibodies and an excipient: “In some embodiments, the disclosure provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-Delta 1 antibody described herein or antigen binding fragment thereof. In some embodiments, the disclosure provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an anti-Delta 1 antibody described herein or antigen binding fragment thereof” (p. 73 lines 22-27); “Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the pharmaceutical composition to the subject, depending upon the type of disease to be treated or the site of the disease [….] For intravenous injection, water soluble antibodies can be administered by the drip method, whereby a pharmaceutical formulation containing the antibody and a physiologically acceptable excipient is infused” (p. 100 lines 14-34).
Regarding claims 9 and 19, Koide et. al. teaches that the antibody or fragment thereof is a single chain antibody (e.g. scFv), wherein a flexible linker is incorporated between the heavy chain and the light chain variable regions variable regions (p. 19 lines 23-28).
Regarding claim 23, Koide et. al. teaches that the anti-delta 1 antibodies of the invention include multispecific antibodies (e.g. bispecific antibodies) (p. 65 lines 3-7, also see p. 16 lines 25-27)(reads on a multispecific antibody comprising a second antibody or fragment thereof).
Claim Rejections - 35 USC § 103- New, necessitated by amendment
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.
Claim(s) 24, 37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019147735 to Koide et. al. published 1 August 2019 (Of record, IDS dated 9/2/2022) as applied to claims 1 and 23 above, and further in view of WO2020227457 A1 to Ganesan et. al. effectively filed 8 May 2019.
Regarding claim 24, Koide et. al. teaches that an embodiment of the antibody is a single chain antibody (e.g. scFv), wherein a flexible linker is incorporated between the two variable regions (p. 19 lines 23-28).
The teachings of Koide et. al. in regards to claims 1 and 23 are in the 103 rejections above. Regarding claim 24, Koide et. al. does not explicitly teach a method of treating cancer comprising an isolated multi-specific antibody or fragment thereof, wherein the isolated multi-specific antibody or fragment thereof comprises a VH and a VL region that are joined by a linker. Regarding claim 37, Koide et. al. does not teach the multi-specific wherein the second of the at least two target antigens in EGFR or CD19. Regarding claim 39, Koide et. al. does not explicitly teach a method of treating cancer comprising administering the multispecific anti-Vδ1 antibody.
These deficiencies are resolved by Ganesan et. al.
Ganesan et. al. teaches multispecific antibodies binding to T Cell Receptor Gamma Variable 9 (TRGV9) comprising a heavy chain and light chain variable regions [0003]. Ganesan et. al. teaches that the TRGV9 is an antigen present on the surface of a gamma delta T cell [0005], [0014]. The antibodies include those with a second binding domain that binds to a second target that is not TGRV9 [0016]. In some embodiments, the bispecific comprises an scFv having a binding specificity for a first epitope and an scFv having a binding specificity for a second epitope [00231]. In some embodiments, the second target is an epitope located on PD-1, PD-L1, EGFR, HER-2, CD19, CD20, CD3 and/or other cancer associated immune suppressors or surface antigens [00231]. Ganesan teaches particular embodiments of an anti-tumor associated antigen (TAA) x Vγ9 bispecific comprising an scFv demonstrating that the bispecific was able to mediate γδ T cell mediated cytotoxicity against TAA-expressing Jurkat cells (See for example Example 4.5, Fig. 9).
Regarding claim 24, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the anti-delta 1 scFv comprising a linker of Koide et. al. in a multispecific or bispecific antibody or the format comprising an scFv as taught by Ganesan et. al. in order to benefit from making the effective anti-delta 1 antibody of Koide et. al. to recruit and activity delta-1 expressing γδ T cells as taught by Koide to the tumor-associated antigen targets in an effective bispecific antibody format as taught by Ganesan et. al. This would have a predictable effect because an artisan would understand from Koide et. al. and Ganesan et. al. that a bispecific binding to γδ T cells may comprise antibody fragments in many formats including an scFv which reduces the number of peptide chains required in the bispecific, and that the scFv format of Ganesan et. al. is effective for targeting tumor cells. Koide et. al. would further lead an artisan to believe there is a reasonable expectation that the anti-delta 1 scFv is effective in a single chain format.
Regarding claim 37, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use an anti-CD19 or an anti-EGFR antibody or fragment thereof as the second antigen binding domain in the anti-delta 1 multispecific antibody in order to benefit from targeting CD19- and EGFR- expressing cancers with recruitment of gamma delta T cells as taught by Ganesan et. al. There is a reasonable expectation of success in substituting the anti-delta 1 scFv of Koide et. al. for the anti- Vγ9 antigen binding domain of Ganesan et. al. because both Ganesan et. al. and Koide et. al. teach antibodies binding to the TCR variable domains of gamma delta T cells in order to recruit gamma delta T cells for cancer cell killing.
Regarding claim 39, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to administer a multispecific (e.g.) bispecific anti-delta 1 antibody as taught by Koide et. al. comprising a binding site for a second target antigen as taught by Koide et. al. in order to treat cancer by targeting gamma delta T cells to a tumor specific antigen as taught by Ganesan et. al. This would have a reasonable expectation of success because Koide et. al. teaches that the anti-delta 1 antibodies are for the treatment of disease such as cancer and may be bispecific; Koide et. al. merely does not explicitly suggest administering a bispecific for the treatment of cancer; given that Ganesan et. al. teach the benefit of tumor cell killing by recruiting gamma-delta T cells using a bispecific antibody targeting a TAA and γδ-TCR chain portion, an artisan would expect that other γδ would also be able to specifically recruit γδ T cells to similar anti-tumor cytotoxic effects.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 9, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 25, and 26 of copending Application No. 17674129 (reference application).
The breadth of the instant claims is described in the Claim Interpretation section above.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application are directed towards an anti-TCR delta variable 1 antibody or antigen-binding fragment thereof comprising light and heavy chain CDR1-3s at least 80% identical to the instant anti-TCR delta variable 1 antibody. Claim 1 recites antibodies with HCDRs of SEQ ID NO: 51, 53, and 55 and SEQ ID NOs: 51, 53, and 59 (at least 80% identical to instant SEQ ID NOs: 40, 28, and 4) and LCDRs of SEQ ID NOs: 79, 80, and 95 and SEQ ID NOs: 79, 80, and 86 (at least 80% identical to instant SEQ ID NOs: 52, DAS, and 16). Claims 2 and 4 recite VH and VL sequences comprising the CDRs of claim 1. Claim 24 is directed to a pharmaceutical composition comprising the antibody. Claims 25-26 is directed to a method of treating a disease or disorder in a subject comprising administering the anti-Vδ1 antibody or fragment thereof of claim 2, wherein the disease or disorder is cancer, an infectious disease, or an inflammatory disease.
Regarding instant claim 19, claim 18 discloses wherein the antibody is an IgG antibody, which reads on full-length antibody.
Regarding claim 9, the claims do not explicitly disclose the VH and VL connected by a linker. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to connect the VH and VL by a linker in order to make, for example an scFv, because an artisan would choose the desired antigen binding domain format the works best for the therapeutic application.
Regarding claim 21, the claims to not explicitly disclose an antibody 80% identical to SEQ ID NO: 112. It would have been obvious, as of the time of filing, to make an antibody with the desired antibody binding domain (scFv) and an IgG domain, resulting in an antibody comprising SEQ ID NO: 112.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the composition of the claims 1-2, 4, in the methods of claims 25-26 in order to treat cancer, an infectious disease, or an inflammatory disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 23, 24, 35, 37 and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 25 and 26 of copending Application No. 17674129 (reference application) in view of WO2020159368 to Van Der Vliet et. al. (cited in IDS dated 9/2/2022) effectively filed 1 February 2019 and Siegers GM, Lamb LS Jr. Cytotoxic and regulatory properties of circulating Vδ1+ γδ T cells: a new player on the cell therapy field? Mol Ther. 2014 Aug;22(8):1416-1422. doi: 10.1038/mt.2014.104. Epub 2014 Jun 4. PMID: 24895997; PMCID: PMC4435582 (cited in IDS dated 9/2/2022).
The teachings of the claims of the ‘129 application are in the NSDP rejection above. Regarding claims 23, 24, 35, 37, and 39, the ‘129 patent does not disclose that the antibody is a multi-specific antibody that binds to at least two targets. This deficiency is partially resolved by WO2020159368 to Van Der Vliet et. al. (cited in IDS), which discloses a method of treating CD-40 expressing cancer by administering an antibody comprising an anti-CD40 domain and an anti-Vγ9Vδ2 receptor binding domain (Abstract). Van De Vliet also teaches the method work by using the anti-Vγ9Vδ2 activating or homing a subset of γδ T cells to the CD40 expressing cancer, facilitating cancer cell death (See p. 21 line 23- p. 23 line 13, Examples 11, 12, 18). Siegers et. al. teaches that Vδ1 T cells are potent anticancer cells and exhibit cytotoxic properties against cancer (p. 1418 Col. 1-2 “Vδ1 T cells are potent anticancer cells” section).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make an anti-cancer bispecific antibody comprising an anti- Vδ1 antibody of ‘129 application and anti-CD40, as in Van Der Vliet in order to target δ1-expressing T cells for the therapeutic application of killing cancer using the cytotoxicity of Vδ1 T cells as taught by Siegers et. al. This would have a likely chance at success because methods of using bispecific antibodies to target immune cells to cancer are well-described in the art and both Van Der Vliet and the ‘129 application are directed to applications of γδ T cell targeting antibodies.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 9, 19, 23, 24, 37 and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51, 57, 59, 60 of U.S. Patent No. 12312408 on May 27 2025 (formerly copending Application No. 18451047) (Of record, cited on IDS dated 11/21/2025).
The breadth of the instant claims is described in the Claim Interpretation section above.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘408 patent teaches a multispecific antibody comprising a variable delta 1 chain of a γδ TCR binding site comprising VHCDRs 1-3 of 51, 53, and 68 (at least 80% identical to instant SEQ ID NOs: 40, 28, and 4) and LCDRs 1-3 of SEQ ID NOs: 79, 80, and 95 (at least 80% identical to instant SEQ ID NOs: 52, DAS, and 16) and a Fc region that comprises an EGFR binding site in the CH3 domain of the Fc region. Claim 57 teaches wherein the vd1 TCR binding site is in a Fab region of the multispecific antibody (reads on instant claim 19). Claims 59-60 teach a pharmaceutical composition and a method of treatment of cancer comprising administering the multispecific antibody. Regarding claims 9 and 24, the claims do not explicitly disclose the VH and VL connected by a linker. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to connect the VH and VL by a linker in order to make, for example an scFv, because an artisan would choose the desired antigen binding domain format the works best for the therapeutic application.
Response to Arguments
Applicant notes that Application 17674129 is the later-filed provisional application (Remarks 11/21/2025 p. 8-9) and requests that the rejection be held in abeyance. This is not persuasive because MPEP 804.I.B.1 does not allow the rejections to be held in abeyance.
Applicant argues that the amended claims are not anticipated or rendered obvious by the claims of the ‘408 patent. This is not persuasive as described in the Claim Interpretation and NSDP rejections, necessitated by amendment, above.
Allowable Subject Matter
Claims 21 and 35 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678