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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US21/61548, filed on 12/02/2021, which claims domestic benefit to US provision application 63/120,356, filed 12/02/2020.
Claim Status
The amendment, filed on 06/02/2023, in which claim 22 is amended and claims 15-16, 20, and 24 are canceled, is acknowledged. Claims 1-14, 17-19, and 21-23 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/10/2025 has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
“qdrenocortical” should read “adrenocortical” - pg 14, line 21
“cholangio carcinorna” should be one word - pg 9, lines 1-2; pg 14, line 23; pg 22, line 20; pg 71, line 20
“polymerosomes” should read “polymersomes” - pg 41, line 26
“ouchterlony" should be capitalized - pg 68, line 16
Capitalization of proper names in listed non-limiting examples of cancer types (e.g. Burkitt, Hodgkin’s, Kaposi, Langerhans, Merkel, Sézary, Waldenstrom, Wilms) - pg 69-70
Appropriate correction is required.
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.
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.
The instant claim is drawn to the composition of claim 1, and further recites wherein the domain that specifically binds to Dsg2 comprises a Dsg2, an anti-Dsg2 antibody or a fragment thereof. The instant specification notes that Dsg2 forms homodimers, therefore, in one embodiment, the Dsg2 binding molecule comprises Dsg2 or a fragment thereof (i.e. a CAR comprising a Dsg2 ECD rather than an anti-Dsg2 antibody) (pg 23, lines 11-13). However, Dsg2 is more likely to form heterophilic interactions with desmocollins (Dscs) based on surface plasmon resonance data (Harrison et al. Proc Natl Acad Sci USA. 2016;113(26):7160-7165; Figure 1A - shown below). This would suggest that generating a CAR with a Dsg2 molecule or fragment thereof would not necessarily be specific for Dsg2 and therefore renders the scope of claim (i.e. binding specificity) indefinite.
For examination purposes examiner has focused on embodiments based on an anti-Dsg2 antibody or fragment thereof.
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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 1-14, 17-19, and 21-23 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.
Regarding claims 1-3 and 8-9,
Claim 1 is drawn to a composition comprising a CAR molecule comprising a Dsg2 binding domain.
Claim 2 recites the Dsg2 binding domain of claim 1 comprises an scFv.
Claim 3 recites the Dsg2 binding domain of claim 1 comprises Dsg2, an anti-Dsg2 antibody or a fragment thereof.
Claim 8 is drawn to a composition comprising a nucleic acid molecule encoding a CAR molecule comprising a Dsg2 binding domain.
Claim 9 recites the Dsg2 binding domain of claim 8 comprises an scFv.
Instant claims 1-3 and 8-9 contain functional language by claiming a genus of CARs with binding domains (described in the specification to include antibodies or fragments thereof - pg 59, lines 6-11) by what they do function - e.g. ability to bind to Dsg2), rather than by what they are (structure - i.e. specific paratope sequence). MPEP 2173.05(g) teaches that "Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C.112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197." In this case, the antigen binding domain is based on the target to which they bind, not the structure of the antibody that would result in the claimed target binding. The instant disclosure does not demonstrate an adequate number of species of the claimed genus nor does it adequately describe the structure required to achieve the claimed function in such a way as to demonstrate to a skilled artisan that applicant was in possession of the genus as claimed at the time of filing.
These Dsg2 binding domain species as disclosed in the instant specification (6D8 antibody and 10D2 antibody - Table 1 and 2) do not adequately describe structure-function relationship which would allow an ordinarily skilled artisan to envision all antibodies within the claimed genus binding molecules specific for Dsg2 as instantly claimed, as the state of the art even several years after the effective filing date of the claimed invention demonstrates that the prediction of epitope binding based on antibody structure was still not fully understood.
For example, Hummer et al. (Curr Opin Struct Biol. 2022;74:102379) teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer et al. teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, ¶ 2). Hummer et al. provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, ¶ 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer et al. acknowledges this in their discussion of future directions stating:
“Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, ¶ 3).
In summary, Hummer et al. teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function. Overall, it is not evident by the disclosure, or the prior art, that applicant was in possession of an adequate number of species of antibodies which bind to the same epitope (mutated Fc domain) as recited within the instant claim. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable generation of antibodies that bind to the same epitope.
Therefore, instant claims 1-3 and 8-9, and subsequent dependent claims 7, 17-19, and 21-23 that do not rectify the issues as discussed above were found to not meet the written description requirement of 35 USC 112(a). To rectify these issues examiner recommends to amend the respective base claims to recite specific binding domain sequences (i.e. collective 6 CDRs that form Dsg2 specific paratopes).
Regarding claims 4-6 and 10-14,
Claims 4 and 10 recite the Dsg2 binding domain (of claim 1 and claim 8, respectively) comprises an antibody or fragment thereof comprising at least one CDR sequences selected from a group consisting of various CDR sequences. Subsequent dependent claim 12 further recites the composition of claim 10 comprising at least one CDR selected from various nucleotide sequences. By broadest reasonable interpretation the claims are drawn to a genus of antibody formulations that need only have at least one of the disclosed CDRs or could have pairings of any species of CDR listed.
Claims 5 and 11 recite the antibody of respective base claims claim 4 and 10, wherein the antibody comprises at least one amino acid sequence selected from species listed in groups (a)-(j), which list individual variable heavy or variable light chain sequences (i.e. drawn to a genus of antibodies that need only have one of the listed VH/VL sequences), including options for sequences have at least 95% identity or at least 80% identity to respective heavy or light chain sequences. Claim 13 similarly recites the above limitations with respective nucleotide sequences for the composition of claim 12 (i.e. need only have at least one of the nucleotide sequences listed for VH/VL domains with options of either 95% or 80% variability). These respective claims therefore encompass a genus of formulations that need only have at least one either the VH or VL domains listed or a sequence with up to 5% or 20% variance.
Claims 6 and 14 recite the compositions of claim 1 or claim 8 respectively, wherein the CAR comprises amino acid sequence (SEQ ID NO: 34 or 36) or nucleic acid sequence (SEQ ID NO: 33 or 35), respectively; or sequences having at least 90% identity or at least 85% identity to said sequences.
MPEP 2163(II)(A)(3)(a)(ii) states that the written description requirement for claimed genus may be satisfied through a sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
The instant specification discloses 2 species of CDR sets with evidence of dsg2 binding (Table 1 and 2), summarized below with respective nucleic acid (NA)/amino acid (AA) SEQ ID NOs (i.e. embodiments with sufficient written description):
SEQ ID NOs: (NA/AA)
HCDRs
LCDRs
Clone
VH
1
2
3
VL
1
2
3
6D8
7/8
1/2
3/4
5/6
15/16
9/10
11/12
13/14
10D2
23/24
17/18
19/20
21/22
31/32
25/26
27/28
29/30
The content at issue and failing to comply with written description requirements:
Regarding claims 4, 10, and 12,
Undisclosed CDR pairings within the individual CDR sequences recited beyond embodiments with sufficient written description (see above).
Species with less than the full complement of 6 CDRs as disclosed (see above).
Regarding claims 5, 11, and 13,
VH/VL sequence swapping (i.e. interchangeability in VH/VL domains) beyond embodiments with sufficient written description (see above).
Sequence variability without reservation (i.e. encompassing critical CDR residues)
Regarding claims 6 and 14,
Sequence variability without reservation (i.e. encompassing critical CDR residues)
The specification does not provide guidance for arriving at antibodies as currently claimed to allow one of ordinary skill in the art to envision all variation within those critical binding paratopes (e.g. up to 5% or 20% variance in full sequence and/or interchangeability in CDR pairings) that would predictably retain Dsg2 binding.
The state of the art near the effective filing date of the claimed invention demonstrates that antibody functionality is dependent on amino acid structure, particularly regarding complementarity of the six CDRs. It is understood by one of ordinary skill in the art that mutations to CDRs is unpredictable and that each construct requires function testing.
Rabia et al. (Biochem Eng J. 2018 Sep 15;137:365-374.) teaches that antibody-antigen binding specificity is primarily mediated by their CDRs within the sequences of variable heavy and variable light chains (Introduction, ¶ 1). Given the chemical diversity possible within combined CDRs alone (~20 different amino acids at ~60 sites), not all combinations can result in viable antibodies suitable for therapeutic applications. Rabia et al. teaches that natural antibody maturation relies on random somatic mutations followed by clonal selection for antibodies with improved affinity and/or with mutations that compensate for destabilizing affinity enhancing mutations (page 366, column 2, ¶ 2). However, it is expected that most somatic mutations that increase affinity, such as those that increase hydrophobicity or charge, can also reduce specificity. For instance arginine in CDRs was identified as the greatest risk factor for non-specific interactions (page 368, column 1, ¶ 5). Based on these teachings, introducing mutations in antibody structure, particularly in the CDR regions, requires thorough testing to ensure suitable binding specificity and antibody stability.
Herold et al. (Sci Rep. 2017;7(1):12276) teaches antigen binding is "affected by each CDR loop differently" and changes thereto "can in principle affect antigen binding affinity in an unpredictable way" (pg. 14, ¶ 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex (pg. 14, ¶ 3).
Furthermore, Koenig et al. (PNAS USA. 2017;114(4):E486-E495) teaches that single amino acid mutations across both VL and VH can alter stability and antibody-antigen binding. In generating a single mutation library in VL and VH chains (Figure 1), Koenig et al. identified mutations distal to CDRs can improve anti-VEGF antibody G6.31 stability (anti-gD tag; enriched in red) and affinity (VEGF; enriched in red), but conserved framework positions including the hydrophobic core and interface residues in addition to a few CDR positions, particularly in HCDR3, exhibited low tolerance to mutation (depleted in blue/ strongly depleted in black). Furthermore, single cysteine mutations or single residue deletions in nearly all residues across VL and VH chains resulted in reduced stability and binding. Therefore, a single mutation, encompassed by the instant claims (variability of 10% sequence identity), let alone full swapping of CDR domains could therefore potentially result in loss of antibody stability and/or binding.
Regarding single domain antibodies (sdAbs) recombinantly-produced from heavy chain variable regions (i.e. sdAb with 3 CDRs instead of 6 CDRs), Wagner et al. (Int J Mol Sci. 2018 Nov 2;19(11):3444) teaches that design of nanobody grafts with CDRs derived from conventional antibodies (VH CDRs) requires careful consideration because conventional antibodies utilize both VH and VL domains for antigenic recognition (page 2, last ¶). A direct CDR grafting approach was observed to produce weak antigen binders (abstract). A second step was required, in which additional affinity maturation steps by panning of synthetic phage libraries was performed generate nanobodies with sufficient antigen binding, resulting several changes in grafted CDR residues (Abstract; Figure 6B). Therefore, based on these teachings it would be unlikely that direct CDR grafting from conventional VH CDRs to a sdAb format without modifications (e.g. as disclosed for Ab5 or as suggested with “or” statements between claimed VH and VL sequences) would predictably generate a functional nanobody.
Moreover, Zabetakis et al. (PLoS One. 2013;8(10):e77678) teaches the highly-variable CDRs embody the specific binding interaction of the antigen-antibody complex (introduction ¶ 2). Through CDR swapping experiments in sdAbs, Zabetakis observed that while swapping framework regions and CDRs will work in some cases to increase thermal stability this can cause unpredictable variability in affinity (i.e. swapping CDRs within sdAbs can change target specificity) (Abstract; Table 1; page 5, column 2, last ¶ ).
Based on prior art, making changes to the CDR sequences of an antibody is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding swapping CDR domains with any reasonable expectation of success nor envisage the breadth of CDR combinations as claimed (e.g. with up to 5% or 20% variance) that would still possess claimed Dsg2 binding. As such, an ordinarily skilled artisan would not have recognized that applicant was in possession of the entire scope of the claimed genus at the time of the effective filing date of the claimed invention. To overcome these rejections, examiner recommends amending the claims to recite full complement of CDR sets with sufficient written description (see above) and to limit sequence variability to regions outside CDR domains (e.g. claim variance in subsequent dependent claims wherein the base claim recites full CDR sequences).
Claim Rejections - 35 USC § 112(a) - Enablement
Claim 22 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The specification, while being enabling for “treating” cancer, does not reasonably provide enablement for “preventing” cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding the prevention of cancer, the America Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (Cancer risk and prevention. American Cancer Society. Accessed January 22, 2025. https://www.cancer.org/cancer/risk-prevention.html. Internet – Wayback Machine). And, while Dsg2 has higher relative expression in certain cancers (WO2015121454A1- Table 5) and modified immune cells expressing cancer antigen specific CARs have been shown as effective in promoting cytotoxic activity against tumor cells suggesting use in cancer treatment, there is no evidence in the prior art that utilizing a Dsg2-CAR enables cancer prevention without undue experimentation. See MPEP § 2146.01.
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 1-3, 7-9, 17-19, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/121454 A1 (herein WO’454) and US 2019/0300604 A1 (herein US’604).
WO’454 teaches methods of developing genetically engineered immune cells for immunotherapy CARs targeting an antigen marker common to both pathological cells and immune cells (abstract). WO’454 teaches an example anti-CD38 scFv CAR, as CD38 is expressed on both T cells and various tumor cells (Figure 1 and 11) and teaches methods of expressing CAR constructs in T cells via lentiviral vector (i.e. nucleic acid molecules) (pg 43, lines 9-14; pg 92, “Screening”). WO’454 also teaches other potential antigenic markers, including Dsg2 as an antigenic marker overexpressed on colon tumor cells (Table 5).
While WO’454 teaches Dsg2 as a potential CAR antigen, WO’454 does not explicitly teach an antigen binding domain specific for Dsg2 to construct said CAR.
US’604 teaches anti-Dsg2 antibodies and their ability to bind to various cancer cells (Examples; Figures 4-5). US’604 teaches Dsg2 is highly expressed in epithelial-derived malignancies (¶ [0005]). US’604 further teaches and said antibodies or antigen binding portions thereof can be used in pharmaceutical compositions with pharmaceutically acceptable excipients for treatment of cancer within an anti-cancer therapy including, but not limited to immunotherapeutic agents (claims 13, 15, and 24).
A skilled artisan would recognize the modular nature of chimeric antigen receptors and be motivated to adapt an antigen and corresponding binding domains based on the expression profile of target cells. Therefore, it would be obvious to one of ordinary skill that a CD38-CAR molecule and nucleic acids thereof as taught by WO’454 can be modified to substitute the anti-CD38 scFv for other known scFv fragments including a known anti-Dsg2 antibody that can bind to tumor cells as taught by US’604 with a reasonable expectation of success of targeting T cells to Dsg2 expressing tumors (i.e. a method for treating cancer).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over WO‘454 and US‘604 as applied to claim 19 above, and further in view of Müller et al. (Front Immunol. 2020;10:3123. Published 2020 Jan 24).
WO’454 and US’604 teach claim 19 as discussed above.
However, neither reference teaches the use of genetically engineered NK cells.
Müller et al. teaches NK cells, contrary to T cells, do not carry the risk of inducing graft vs. host disease (GvHD), allowing application of donor-derived cells in an allogenic setting. Hence, unlike autologous CAR-T cells, with optimized transfection methods therapeutic CAR-NK cells can be generated as an off-the-shelf product from healthy donors (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute a CAR-T cell as taught by the combined teachings of WO’454 and US’604 with a CAR-NK cell as this would improve scalability while reducing the likelihood of patient rejection of engineered cell-therapies as taught by Müller.
Allowable Subject Matter
Species with sufficient written description, CARs comprising Dsg2 targeting CDR sets as discussed above (i.e. encoded within clones 6D8 or 10D2), are free from prior art.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647