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 .
DETAILED ACTION
Amendments
In the reply filed 06/22/2026, Applicant has amended claims 116 and 134.
Claim Status
Claims 116-117 and 119-134 are pending.
Claims 124-125 and 128-129 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 05/04/2023.
Claims 116-117, 119-123, 126-127 and 130-134 are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 116, 119-123, 126-127, 130 and 133 under 35 U.S.C. 103 as being unpatentable over Kararoudi et al., (bioRxiv preprint doi: https://doi.org/10.1101/743377; published August 22, 2019. Downloaded on 2/2/2024. P. 1-16. Prior art of record) in view of Tang et al., (Am J Cancer Res. 2018;8(6):1083-1089. Prior art of record) and Li et al., (Cell Stem Cell. 2018; 23: 181-192, cited in IDS 07/26/2022) is withdrawn in light of Applicant’s amendment to claim 116 to recite new limitation “wherein a polynucleotide encoding the scFv comprises at least 80% sequence identity to SEQ ID NO: 29”, which is not taught by the cited art.
The prior rejection of claim 117 under 35 U.S.C. 103 as being unpatentable over Kararoudi et al., (bioRxiv preprint doi: https://doi.org/10.1101/743377; published August 22, 2019. Downloaded on 2/2/2024. P. 1-16. Prior art of record) in view of Tang et al., (Am J Cancer Res. 2018;8(6):1083-1089. Prior art of record) and Li et al., (Cell Stem Cell. 2018; 23: 181-192, cited in IDS 07/26/2022), and further in view of Suzuki et al., (Nature. 2016; 540: 144-149 and Extended Data Figure 1. Cited in IDS 07/26/2022) is withdrawn in light of Applicant’s amendment to claim 116 to recite new limitation “wherein a polynucleotide encoding the scFv comprises at least 80% sequence identity to SEQ ID NO: 29”, which is not taught by the cited art.
The prior rejection of claims 119-121 and 131-132 under 35 U.S.C. 103 as being unpatentable over Kararoudi et al., (bioRxiv, doi: https://doi.org/10.1101/743377; published August 22, 2019. Downloaded on 2/2/2024. P. 1-16. Prior art of record) in view of Tang et al., (Am J Cancer Res. 2018;8(6):1083-1089. Prior art of record) and Li et al., (Cell Stem Cell. 2018; 23: 181-192, cited in IDS 07/26/2022), and further in view of Oyer et al., (Cytotherapy. 2016; 18: 653–663. Prior art of record) is withdrawn in light of Applicant’s amendment to claim 116 to recite new limitation “wherein a polynucleotide encoding the scFv comprises at least 80% sequence identity to SEQ ID NO: 29”, which is not taught by the cited art.
The prior rejection of claim 134 under 35 U.S.C. 103 as being unpatentable over Kararoudi et al., (bioRxiv preprint doi: https://doi.org/10.1101/743377; published August 22, 2019. Downloaded on 2/2/2024. P. 1-16. Prior art of record) in view of Tang et al., (Am J Cancer Res. 2018;8(6):1083-1089. Prior art of record) and Li et al., (Cell Stem Cell. 2018; 23: 181-192, cited in IDS 07/26/2022), and further in view of Lee et al., (US PGPub No. 2018/0163176. Cited in IDS 07/26/2022) is withdrawn in light of Applicant’s amendment to claim 134 to recite new limitation “wherein the polynucleotide encoding the scFv comprises SEQ ID NO: 29”, which is not taught by the cited art.
New 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 116-117, 119-123, 126-127 and 130-133 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically, the amended claims recite new limitation “wherein a polynucleotide encoding the scFv comprises at least 80% sequence identity to SEQ ID NO: 29” (see independent claim 116, underlined by examiner). However, the specification only discloses two anti-CD33 scFv polynucleotide sequences (instant SEQ ID NOs: 18 and 29. It is noted that the specification also discloses two polynucleotide sequences corresponding to anti-CD33 scFv that are located within polynucleotide sequences encoding the CAR, i.e., 1329-2128 of SEQ ID NO: 22 and 1329-2129 of SEQ ID NO: 23 that are identical to SEQ ID NOs: 18 and 29, respectively).
Under the new Written Description Guidelines for antigen binding proteins molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
SCOPE OF THE INVENTION
Independent claim 116 encompasses a genus of method of genetically modifying a primary or expanded NK cell or NK T cell comprising infecting the cell with a genus of AAV comprising a genus of polynucleotide sequence encoding an anti-CD33 CAR that comprises a genus of polynucleotide sequence encoding the scFv of the CAR that comprises at least 80% sequence identity to SEQ ID NO: 29.
With the instant SEQ ID NO: 29 consisting of 801 nucleotides, the claimed scope encompasses a genus of polynucleotide sequences in which up to 160 nucleotides can be added, deleted or mutated to any nucleotide, at any position and in any combination. The claimed scope thus encompasses an astronomical number of polynucleotide sequences, that may encode a scFv that specifically binds to a CD33.
However, the specification only discloses two polynucleotide sequences that encode anti-CD33 scFv (i.e., instant SEQ ID NOs: 18 and 29. It is noted that SEQ ID NO: 18 has 87% identity to SEQ ID NO: 29).
Dependent claims 117, 119-123, 126-127 and 130-133 encompass the arrangement of the AAV vector, the incubation of cells prior to and following infection, the MOI of the AAV, electroporation of RNP complex, type of AAV and Cas9 endonuclease. However, the specification only discloses two anti-CD33 scFv polynucleotide sequences (i.e., instant SEQ ID NOs: 18 and 29) in regard to the claimed genus of polynucleotide sequences encoding the scFv.
ACTUAL REDUCTION TO PRACTICE
As stated supra, the independent claims and dependent claims have a much broader scope compared to that is disclosed in the specification. Specifically, Applicant has disclosed in the specification merely two anti-CD33 scFv polynucleotide sequences (i.e., instant SEQ ID NOs: 18 and 29). Thus, Applicant fails to show actual reduction to practice the broad scope as being claimed.
DISCLOSURE OF STRUCTURE
The Applicant has provided two anti-CD33 scFv polynucleotide sequences (i.e., instant SEQ ID NOs: 18 and 29). Certainly, a skilled artisan could mutate the polynucleotide sequences based on SEQ ID NO: 29 to obtain a polynucleotide sequence variant that is at least 80% identical to SEQ ID NO: 29. However, neither the specification nor the art indicate a relationship between the structure of the claimed genus of polynucleotide sequence variants and the ability to specifically binds to CD33.
Thus, the scope of the claims does not commensurate with the limited number of species (merely two sequences) provided by the disclosure with regard to the extremely large number of variants broadly encompassed by the claims. Since the polynucleotide sequence encodes the amino acid sequence of a scFv that determines its structural and functional properties (e.g., antigen binding ability of the scFv in the instant claims), predictability of which changes can be tolerated in a polynucleotide sequence and obtain the desired scFv binding activity requires a knowledge of and guidance with regard to which nucleotides in the polynucleotide sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the scFv's structure relates to its function. However, in this case the disclosure is limited to the two specific polynucleotide sequences encoding the anti-CD33 scFv.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications as well as the positions within a polynucleotide sequence, as encompassed by the instant claims, where nucleotide modifications can be made with a reasonable expectation of success in preserving the desired binding activity to CD33. The result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to a modification for a given polynucleotide sequence to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass modifications of instant SEQ ID NO: 29, because the specification does not establish: (A) regions of the polynucleotide sequence which may be modified without effecting antigen specificity; (B) the general tolerance of CDRs to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any CDRs with an expectation of obtaining the desired biological function capable of binding to CD33, and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)).
Without sufficient guidance, determination of exact nature of the polynucleotide variants having the desired CD33-binding characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731,8 USPQ2nd 1400 (Fed. Cir, 1988).
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, two polynucleotide sequences are provided.
Accordingly, if the skilled artisan sought to generate the claimed genus of polynucleotide variants, they would first need to know which sequences in the polynucleotide could be chosen to modify or combine and still be able to predictably produce a functional anti-CD33 scFv. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of polynucleotide sequences that encodes an anti-CD33 scFv.
The breadth of the claims encompasses a genus of polynucleotide sequences in which up to 160 nucleotides can be added, deleted or mutated to any nucleotide, at any position and in any combination, that encode a scFv that specifically binds to a CD33.
The present specification provides no guidance nor description to any rationale in choosing how to choose modifications, substitutions or positions of the nucleotides, therefore the skilled artisan would not know what rational approach to take to make modifications with any predictable outcome on binding CD33. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of a larger genus of polynucleotide sequences encoding an anti-CD33 scFv. Otherwise, the Written Description guidelines suggest that the applicant is entitled to only the species specifically recited as having this activity. Moreover, even when several species are disclosed (only two in instant case), these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of using the claimed invention is not well established. Although the mutagenesis of polynucleotide sequence is routine and conventional, one of skill in the art would neither expect nor predict the appropriate functioning of binding to CD33 produced according to the claimed genus of polynucleotide sequences as broadly as is claimed.
Fujiwara et al., (Biochemical and Biophysical Research Communications. 2020; 527: 350-357) evidences that “Although antigen specificity and reactivity of CAR-T cells are defined by CAR expression level and affinity, information on optimizing the scFv structure that defines CAR avidity is lacking. Here, we investigated the impacts of scFv substitution and structural modification in CAR on receptor expression and antigen recognition properties. Four CARs with distinct scFvs targeting the same antigen were unexpectedly separated into a CAR expressed on T cells and bound to the antigen, CARs that did not show antigen-binding because of cell surface aggregation, and a rarely expressed CAR. Among the scFv structural modifications of CARs, changes in the Fv order and linker did not noticeably affect CAR expression or antigen-binding. In contrast, complementarity-determining region (CDR)-grafting to the stable framework region in Fv dramatically improved the surface expression level of non-producible CAR. These results revealed that CAR expression efficiency and stability on T cells are influenced by the Fv structure” (see e.g., abstract). Thus, Fujiwara evidences that the Fv structure, encoded by the polynucleotide sequence, determines the CAR expression efficiency and stability on T cells, and thus the specific binding to the CD33 target.
Applicant has claimed a genus of polynucleotide sequences encoding an anti-CD33 scFv, yet the specification has only disclosed two such sequences that have the claimed binding function. Independent of how these specific sequences were arrived upon by Applicant, a polynucleotide sequence cannot encode a scFv and predictably has functional CD33 binding capability. Because Applicant has no manner a priori to predict what mutations, combinations and positions can be modified to make a polynucleotide sequence to encode a functional anti-CD33 scFv, the genus of polynucleotide sequences claimed by Applicant cannot be predictably made or used by the ordinary artisan.
Furthermore, functionally defined genus claims (e.g., a scFv that specifically binds to CD33) can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
CONCLUSION
The Examiner concludes that there is insufficient written description of the instantly claimed genus of polynucleotide sequences that has at least 80% identity to SEQ ID NO: 29 and encodes an anti-CD33 scFv. Specifically, Applicant has only provided two such sequences with the claimed function, thus does not provide sufficient number of species to represent the entire scope of the claimed extremely broad genus of sequences. Therefore, the Examiner concludes that there is insufficient written description to show that Applicant was in possession of the entire scope of the claimed genus of polynucleotide sequences that has at least 80% identity to SEQ ID NO: 29 and encodes an anti-CD33 scFv.
Response to Traversal:
Applicant’s arguments filed on 06/22/2026 are acknowledged.
Applicant argues that the cited prior art do not teach or suggest a polynucleotide sequence encoding the scFv being at least 80% identical to SEQ ID NO: 29 or the polynucleotide sequence encoding the scFv being SEQ ID NO: 29 (Remarks, p. 6-13).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejections set forth in the prior Office action mailed on 03/20/2026 have been withdrawn. However, as necessitated by amendment, a new ground of rejection under 35 USC § 112(a) Written Description has been made as discussed above.
Allowable Subject Matter
Claim 134 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. Specifically, the prior art does not teach nor reasonably suggest a polynucleotide encoding the scFv comprising SEQ ID NO: 29 and specifically binding to CD33.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JIANJIAN ZHU/Examiner, Art Unit 1631
Prosecution Insights