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 .
Information Disclosure Statement
The information disclosure statement filed 09/20/2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Specifically, no copies of the cited non-patent literature or foreign documents have been submitted. The IDS has been placed in the application file, but the information referred to therein has not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834.
The examiner has noted that the claims reference SEQ ID NOs: 90-95 (Claims 14 and 15), and the specification recites sequences titled SEQ ID NOs: 62-100 (Pg 157-161), however no such sequences are present in the Sequence Listing XML, which contains only SEQ ID NOs: 1-61.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The drawings are not of sufficient quality to permit examination. The majority of the text in the figures is indecipherable, and many of the smaller and/or finer details are too blurry to interpret. Accordingly, replacement drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to this Office action. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Claim Objections
Claims 1 and 14-15 are objected to because of the following informalities:
Claim 1 recites “MUCI” (with the letter/roman numeral “I” instead of the number “1”), whereas the remainder of the claims and the specification recite instead “MUC1” (with the number “1”) in reference to the same protein. For consistency, Claim 1 should read “MUC1”.
As pointed out above, Claims 14-15 recite SEQ ID NOs: 90-95, however no such sequences are present in the sequence listing.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 3 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 3 depends from Claim 1, which requires a complete set of heavy chain and light chain CDRs belonging to a conventional antibody. However, the claim recites that the antigen binding domain can be a Camel Ig, Ig NAR, and single domain antibody – all of which comprise heavy-chain-only binding domains whose architecture differs from that of a conventional antibody. Accordingly, it is unclear what constitutes an “antibody or antigen binding domain thereof” comprising the CDRs of claim 1 wherein the binding domain is a Camel Ig, Ig, NAR, or single-domain antibody.
Claim 3 is further rejected for containing the trademark/trade name Nanobody®. 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 single domain antibody and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112
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 1-16, 18-20, 26-27, 30-31, and 37-39 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. This is a written description rejection.
Summary
The claims are drawn to a vast genus of humanized anti-Tn-MUC1 antigen binding domains comprising CDRs derived from a murine anti-Tn-MUC1 antibody and functionally requiring that said antibodies possess a faster dissociation rate constant than the non-humanized version. However, there is insufficient disclosure to support possession of anti-Tn-MUC1 antigen binding domains comprising variability within the recited CDR sequences or antibodies possessing the functional requirement of a “faster dissociation rate constant” beyond the particular pairs of complete VL/VH sequences disclosed in the specification and exemplified in the CAR sequences of Claim 17. Further, regarding Claim 15, it could not be determined from the disclosure if anti-Tn-MUC1 scFvs comprising SEQ ID NOs: 92 or 95 belong to the claimed genus.
Scope of the claimed genus
Each of Claims 1-16, 18-20, 26-27, 30-31, and 37-39 require a humanized antigen binding domains specific for aberrantly glycosylated MUC1 protein comprising six CDRs with 90% identity to the recited SEQ ID NOs wherein said antigen binding domain has a “faster dissociation rate constant” for its antigen “as compared to a non-humanised version” of said binding domain. The unspecified variation allowed within the CDR sequences encompasses a massive number of potential anti-Tn-MUC1 antibodies, each potentially comprising substitutions, deletions, and insertions of any amino acid at any position within the claimed sequences.
Claims 5, 14, and 16 each specify variable heavy and/or light chains having 90% identity to the recited sequences, but fail to further limit that variability within the CDR domains as recited in Claim 1 and allow for countless unspecified changes and combinations of mutations to the framework regions of the claimed antibodies.
Claim 2 further specifies the complete CDR sequences but fails to restrict the sequences of the humanized framework region, thereby encompassing countless possible combinations of template framework sequences and back-mutations made to said sequences. As shown in Fig. 6 of the instant disclosure, the framework sequences contribute the specific binding properties of the antigen binding domain as required by the instant claims. Claim 6 allows for mix-and-match pairings of the recited VL and VH sequences, encompassing 36 possible species of humanized anti-Tn-MUC1 antigen binding domains that may or may not possess the functional requirements of having a “faster dissociation rate constant” for an epitope “as compared to a non-humanised version”.
State of the Prior Art
As was well known in the antibody art, the formation of an intact antigen binding site in a conventional antibody typically 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 (reviewed in Sela-Culang et al. Frontiers in Immunology, 4 (2013): 302.; PTO-892). It is generally understood that all six CDRs in combination and in a specific order (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) are required to convey an antibody’s specificity to its target, and that neither the CDRs themselves nor individual VH and VL domains are interchangeable.
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 1982 (Proceedings of the National Academy of Sciences 79.6 (1982): 1979-1983.; PTO-892). 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 (Abstract).
Although more recent advances in computational modelling of CDRs have led to improvements in rational mutagenesis of antibodies, the overall effects of any given mutation on antibody function remain unpredictable. For example, Chiu et al. 2019 (Antibodies, 8(4), 55.; PTO-892) teaches that although modeling has proven accurate for framework region sequences, CDR modeling requires further development and improvement (Pg. 6, ¶2). In particular, prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (Pg. 6, ¶2). Chiu further states “despite the obvious development in algorithms and computer power, the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate” (Pg. 11, ¶ 2).
Chiu further discusses the state of the art as it relates to antibody humanization and highlights the importance of VH-VL pairing to antigen-binding affinity (§2.1.3). For example, even in cases where structural analysis indicated that all the interactions between the antibody CDRs and the antigen were conserved, changes in the relative orientation of the VH and VL domains can cause a dramatic loss in antibody affinity – and a modification as small as a single back-mutation in the framework region has the potential capacity to completely restore this diminished affinity (Pg. 14, ¶3). Chiu further teaches the utility of back-mutations more generally, as “straightforward CDR grafting may result in reduced target binding even if the VH-VL interface residues are preserved” (Pg. 16, §2.1.4), and back-mutations in the framework region can both modulate binding affinity and improve antibody expression. However, although some residues are frequently targeted for back mutation – such as those in the vernier zone known to influence the structure of CDRH2 – the importance of these residues depends largely on the particular CDRs of the grafted binding domain, and it is “not always the case” that such mutations will be of benefit to the antigen-binding affinity/function.
Regarding the particular anti-Tn-MUC1 5E5 derived antibodies to which the instant claims are drawn, the varying impact on binding affinity of different VH/VL pairs and even minor changes in the amino acid sequence of humanized framework regions is highlighted both in the prior art and the instant application. For example, the “MB-024” CAR, comprising the “13-P16” scFv (VL and VH according to instant SEQ ID NOs: 52 and 53, respectively), had among the fastest dissociation rates of the instantly disclosed humanized antibodies (see instant Fig. 6). However, Van Berkel et al. 2015 (WO 2015/159076 A1; PTO-892) discloses humanized 5E5-derived “Ab1” comprising a light and heavy chain with 98.2% and 93.1% identity to instant SEQ ID NOs: 52 and 53, respectively (see alignment with Van Berkel SEQ ID NOs: 31 and 9 below). Yet this antibody (“Ab1”) has increased binding affinity to Tn-MUC1 relative to parent mouse antibody 5E5 (see Van Berkel Pg. 225, Table 2), despite sharing identical CDRs and high sequence identity to the instantly claimed antigen binding domains.
VH – Instant SEQ ID NO: 52; Van Berkel SEQ ID NO: 31; 98.2% Identity
SEQ52 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGDQKNYLTWYQQKPGQPPKLLIFWASTR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||:|||||
VB-31 1 DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGDQKNYLTWYQQKPGQPPKLLIYWASTR 60
Qy 61 ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK 113
|||||||||||||||||||||||||||||||||||||||||||||||||:|||
Db 61 ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKVEIK 113
VH – Instant SEQ ID NO: 53; Van Berkel SEQ ID NO: 9; 93.1% Identity
SEQ53 1 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDHAIHWVRQAPGQGLEWMGHFSPGNTDIKY 60
||||||||||||| ||||||||||||||||||||||||||||| ||||||||||||||||
VB-9 1 QVQLVQSGAEVKKTGSSVKVSCKASGYTFTDHAIHWVRQAPGQALEWMGHFSPGNTDIKY 60
SEQ53 61 NDKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCKTSTFFFDYWGQGTTVTVSS 116
|||||||||:| |:| ||||||||||||||||:||||||||||||||||| |||||
VB-9 61 NDKFKGRVTLTVDRSMSTAYMELSSLRSEDTAMYYCKTSTFFFDYWGQGTMVTVSS 116
Moreover, the six humanized 5E5 antibodies described in Van Berkel are the result of pairing each of three different heavy chains with each of two different light chains. Yet, despite these common sequences, the resulting antibodies from these mix-and-match pairings encompasses a wide range of binding affinities – both greater and lesser than the parent mouse antibody – as well as expression efficiencies (see Van Berkel Table 2).
Similar to the prior art, the instant specification highlights the impact on antigen binding function caused by only minor changes in the framework region. Notably, all of the instantly disclosed antigen binding domains comprise the 5E5 CDRs grafted onto the same humanized framework region and vary by only a handful of back-mutations (see instant specification Pg. 57-61; Tables 4-7; § Humanization of 5E5 VH and VL). However, scFvs from only six of the 24 VH/VL pairs screened retained selectivity for Tn-MUC1 peptide binding (Example 2; Table 8; Pg. 67, lines 21-22), and of these binders, two species “16P4” and “13P16” possessed considerably faster off rates than the rest (Table 15; Pg. 79, lines 23-26).
Description of representative species in the specification
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 disclosure reports 24 scFvs (Table 8) resulting from various combinations of 4 VL chains and 6 VH chains (Table 6) – all comprising the same germline sequences each with varying numbers of back-mutated residues. Of these, six were determined to have retained selectivity for the Tn-MUC1 peptide (Example 2; Table 8; Pg. 67, lines 21-22). Fig. 6 reports the binding affinities for four of these six scFvs relative to mouse 5E5 control (“23-P1”). Of these, while all four tested had faster dissociation constants relative to sTn 35-1 peptide binding, only scFvs “16-P4” and “13-P16” have faster dissociation constants than 5E5 relative to Tn peptide 65-1 and 96-1 binding.
The remaining two scFvs (11P12 and 13P24; corresponding to scFvs comprised within SEQ ID NOs: 92 and 95, respectively, as recited in Claims 14-15) are demonstrated to have KDs situated between that of 13P18 and 11P6 (Table 15), but no comparison to the murine 5E5 is provided. Accordingly, it is unclear whether a CAR comprising SEQ ID NOs: 92 or 95 (corresponding to scFvs of 11P12 and 13P24, respectively) belongs to the claimed genus of an antigen binding domain “that binds one or more epitopes of an aberrantly glycosylated MUC1” wherein said antigen binding domain binds said epitope “with a faster dissociation rate constant (kd) as compared to a non-humanised version”.
One of ordinary skill in the art would not reasonably consider a disclosure of a mere 4 species satisfying all claim limitations among 24 tested – all of which comprising high levels of sequence identity to one another – representative of the massive breadth 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 specificity and affinity.
Although screening methods employed for target binding (Example 2) and affinity characterization (Example 4) are disclosed, the humanized sequences provided are not structurally characterized and the framework region back-mutations employed were chosen based on undisclosed “in-house collated evidences rules for the importance of certain framework positions in the likely maintenance of CDR conformation”. The specification provides no guidance on how the underlying sequence of these humanized scFvs or their structure contributes to the noted differences in binding affinity for particular MUC1 peptides nor how to humanize an antibody comprising the 5E5 CDRs such that the dissociation constant is faster than the parent antibody, while preserving its Tn-MUC1 specificity. Accordingly, the disclosure fails to convey to one of ordinary skill in the art that applicants were in possession of the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 7-13, 18-20, 26-27, 30-31, and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Posey and June 2020 (US 2020/0306304 A1; Priority to 03/27/2019; PTO-892), herein “Posey”, and in view of Van Berkel et al. 2015 (WO 2015/159076 A1; PTO-892), herein “Van Berkel”, and Ghorashian et al. 2019 (Nature medicine, 25(9), 1408-1414.; PTO-892), herein Ghorashian, and as evidenced by the instant specification.
Regarding instant Claims 1-2 and 7, Posey teaches a CAR comprising an antigen binding domain specific for aberrantly glycosylated Tn-MUC1 (¶0620; ¶0665) wherein the anti-Tn-MUC1 antigen binding domain comprises a VH and VL of the 5E5 (¶0620; Table 8), which comprises each of the instantly claimed CDRs (as acknowledged in the instant specification (SEQ ID NOs: 28-33; Pg. 17, last ¶; Pg. 58, last ¶): “All ten humanized chains retained the complete murine CDRs found in the respective 5E5 VH and VL chains”)
Further regarding instant Claim 1, Posey teaches the CAR can comprise humanized variants of the 5E5 binding domain and further suggests that “the humanized Tn-MUC1 binding domain is derived from any one of the humanized 5E5 heavy and light chain sequences disclosed in PCT Publication No. WO2015/159076” (¶0188).
Regarding instant Claims 3-4, Posey teaches the antigen binding domain of the CAR is an scFV (Table 2).
Regarding instant Claims 8-9, Posey teaches the CAR comprises a transmembrane domain isolated from CD8α (¶0408; Table 2).
Regarding instant Claims 10-11, Posey teaches the CAR comprises a costimulatory domain isolated from 4-1BB (¶0409; Table 2).
Regarding instant Claims 12-13, Posey teaches the CAR comprises an intracellular signaling domain isolated from CD3ζ (¶0410; Table 2).
Regarding instant claims 19-20, Posey teaches polynucleotides encoding the anti-Tn-MUC1 CAR and vectors comprising said polynucleotides (§ Nucleic Acids and Expression Vectors, pg 34-39).
Regarding instant Claim 26, Posey teaches retroviral packaging cells (i.e. “vector producer cells”) comprising nucleic acids encoding the anti-Tn-MUC1 CAR cloned into a MSGV retroviral vector (¶0596).
Regarding instant Claims 27 and 31, Posey teaches T cells are transduced with retroviral vectors encoding the anti-Tn-MUC1 CAR, resulting in Tn-MUC1-CAR T cells (¶0596).
Regarding instant Claim 30, Posey teaches pharmaceutical compositions comprising the Tn-MUC1-CAR T cells (¶0561).
Regarding instant Claim 37, Posey teaches a method of treating a MUC1 associated cancer comprising administering a therapeutically effective amount of a composition comprising immune cells expressing an anti-Tn-MUC1-CAR (Posey Claim 70). Posey further teaches that the binding domain of the CAR is specific to aberrant glycoforms of MUC1 (¶0663) and that these aberrant glycoforms are prevalent in tumor cells (§ Method of Treatment; ¶0393).
Regarding instant Claims 38-39, Posey teaches the TN-MUC1-CAR T cells exhibit potent cytotoxicity towards breast cancer cells in vitro and in vivo (Example 4, “Tn-MUC1-Specific CART Cells are
Efficacious In Vitro and in Xenograft Models”; ¶0603-0604), resulting in a reduced tumor volume (Fig. 5; i.e. “decreasing the number of cancer cells”), and that all breast cancer tumor subtypes have aberrant glycosylation of MUC1 (¶0600, ¶0611).
Posey does not teach that the humanized MUC1 antigen binding fragment has a “faster dissociation rate constant (Kd) as compared to a non-humanised version”. These deficiencies are cured by Van Berkel and Ghorashian.
Van Berkel teaches humanized anti-Tn-MUC1 antibodies comprising CDRs identical to those of murine Tn-MUC1 antibody 5E5 (Pg. 224, Example 12).
Van Berkel teaches that humanized antibodies Ab3 and Ab4 have lower affinity for Tn-MUC1 than the mouse 5E5 antibody (Pg. 225, Table 2).
Van Berkel teaches that the Kd of the humanized antibody is at least 10-6 M (Van Berkel claim 3), which is greater (i.e. “faster”) than the Kd of the mouse 5E5 binding domain (as evidenced by instant Fig. 6).
Ghorashian teaches an anti-CD19 CAR comprising an scFv having a higher KD (faster off-rate) for its antigen than the commonly employed FMC63 binding domain (Pg. 1408, col. 2, ¶1). Ghorashian teaches that this CAR with reduced target affinity showed equivalent cytotoxic activity against low-density antigen, and had significantly greater antigen-specific proliferation (Pg. 1408, col. 2, ¶1; Fig. 1) and increased persistence (Pg. 1413, ¶1). Ghorashian concludes: “Together, these results indicate that, under conditions designed to give CAR T cells a numeric disadvantage, low-affinity CAR T cells mediate enhanced antitumor responses and expansion relative to high-affinity CAR T cells” (Pg. 1409).
It would have been obvious to one of ordinary skill in the art to substitute the generic humanized 5E5 binding domain in the CAR taught by Posey with, for example, scFvs derived from the humanized anti-Tn-MUC1 antibodies Ab3 or Ab4 of Van Berkel, each of which has lower affinity for Tn-MUC1 than parent mouse antibody 5E5. The skilled artisan would have been motivated to choose the low-affinity Tn-MUC1 binding domains because Ghorashian teaches that low-affinity CAR T cells have enhanced expansion and antitumor responses relative to high-affinity CAR T cells.
Allowable Subject Matter
Claim 17 is 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.
The following is a statement of reasons for the indication of allowable subject matter:
CARs comprising humanized anti-Tn-MUC1 scFvs with a faster dissociation rate constant compared to a non-humanized version of said scFvs comprising the specific pairs of VH and VL sequences comprised within instant SEQ ID NOs: 58-61 are free of the prior art of record.
The nearest prior art is considered to be Posey and June 2020 (US 2020/0306304 A1; Priority to 03/27/2019; PTO-892) and Van Berkel et al. 2015 (WO 2015/159076 A1; PTO-892). As summarized above, Posey teaches anti-Tn-MUC1 CARs comprising an scFv derived from the mouse 5E5 Tn-MUC1 antibody. Posey further suggests that said CARs could comprise humanized variants according to the Van Berkel reference (WO 2015/159076 A1). Van Berkel itself teaches humanized variants of the murine 5E5 Tn-MUC1 antibody and further teaches variants Ab3 and Ab4 which have reduced affinity for Tn-MUC1 relative to parent 5E5. However, neither Posey nor Van Berkel teach or suggest paired VH/VL sequences comprised within the CARs of instantly claimed SEQ ID NOs: 58-61.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643