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 .
Alternative Names
CD7 is also commonly known as GP40, Leu-9, TP40 and TP41.
Claim Interpretation
Claim 13 recites in lines 2 and 3, “an amino acid sequence of said… scFv”. This is being interpreted as meaning that as few as two consecutive amino acids, i.e., an amino acid sequence, of each scFv must be identical. There is no requirement that the full scFv amino acid sequences be identical to each other.
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:
1) Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. See Figure 3E.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
2) Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). The sequence GGGGS appears in the third lines of [0092]-[0094] and must be accompanied by a SEQ ID NO:.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The Declaration by B. D. Grimshaw cited in the IDS filed 6/13/2024 could not be located in this or either of the priority applications. As a result, it has been lined-through as not considered.
Specification
The disclosure is objected to because of the following informalities: The Abstract defines the abbreviation CAR as “chimeric activating receptor”, while the specification defines CAR as “chimeric antigen receptor” (start of [0003]). The definition of an abbreviation should be consistent throughout the application. Therefore, either the abstract or specification should be changed for consistency. In [00188], line 11, “I n” should be “In”.
Appropriate correction is required.
The use of the term RetroNectin in [0158], Amaxa in [00159] and FlowJo in [00161], each of 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.
Applicant is encouraged to review the specification for other occurrences of trade names or marks.
Claim Rejections - 35 USC § 112(a)
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 1-20 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.
The claims are drawn to a method of producing an engineered immune cell expressing a chimeric antigen receptor (CAR) targeting CD7 and expressing a CD7 antibody target-binding molecule linked to an endoplasmic reticulum (ER) or Golgi localizing domain. Claim 1 is generic to the ER or Golgi localizing domain and structure of the antibody domain. The expressed target-binding molecule prevents fratricide of the engineered immune cell when the immune cell is cultured leading to expression of the CAR. Dependent claims further define the antibody, e.g., that it is an scFv and/or comprises particular VH and VL or CDR1-3 thereof (claims 2-6, 13-16, 19-20). Claim 7 limits the localizing domain to an ER/Golgi localizing domain of SEQ ID NO: 8, 9 or 10. Claims 8-11 further define the CAR domains. Claim 17 requires the expansion or function of the engineered immune cell not to be affected when the first and second nucleic acids are introduced into the cell.
For the protein encoded by the first nucleic acid, the specification discloses a target-binding molecule where the target is CD7 and the molecule comprises a first antibody that specifically binds to CD7 and which is a scFv and the endoplasmic reticulum (ER) or Golgi localization domain having the sequence of SEQ ID NO: 8, 9 or 13 (Table 3 and [0157] and Fig. 3E). For the CAR encoded by the second nucleic acid, the specification discloses only a scFv antibody that specifically binds CD7 ([0157] and [0175] and Fig. 2A). A nucleic acid encoding the CAR and a nucleic acid encoding a target-binding molecule, wherein the CD7-binding domain of each is a scFv, and for the target-binding molecule, wherein the localization domain has the sequence of SEQ ID NO:8, 9 or 10 meets the written description provision of 35 USC 112(a). However, neither the specification nor the dependent claims provide sufficient additional structure or a structure/function correlation to provide an adequate written description of the genera of combinations of: (i) a target-binding molecule comprising an antibody (e.g., single chain variable fragment (scFv); F(ab’)2, single domain antibody and others) that specifically binds to CD7 linked to a structurally undefined ER of Golgi localization domain, with the requirement that the target-binding molecule prevents fratricide of the engineered immune cell expressing ii) a CAR comprising a genus of second antibodies that specifically bind CD7. None of target-binding molecules or CARs comprising these other antibody structures or other ER/Golgi localization domains meets the written description provision of 35 USC 112(a). The specification does not identify 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. Further, the prior art discussed below shows that the intrabody technology was unpredictable and it cannot simply be applied to any type of protein or all antibodies. The skilled artisan would not have reasonably concluded at the time of the invention that applicant was in possession of a genus of undefined target-binding molecules linked to an ER or Golgi localizing domain comprising a first antibody that specifically binds to CD7 as required in claim 1 or to a genus of CD7-binding CARs for the engineered immune cell.
Example 1 specifically teaches "CD7 was targeted with a second-generation CAR (anti-CD7-41BB-CD3ζ.) but CAR expression in T lymphocytes caused fratricide, owing to CD7 present in the T cells themselves. To downregulate CD7 and control fratricide, a new method (Protein Expression Blocker, PEBL), based on an anti-CD7 single chain variable fragment coupled with an intracellular retention domain was applied. Transduction of anti-CD7 PEBL resulted in virtually instantaneous abrogation of surface CD7 expression in all transduced T cells…." (paragraph [0149]). "FIG. 3A - FIG. 3I illustrate expression of anti-CD7 CAR in human peripheral blood T-cells results in fratricide which is prevented by CD7 downregulation." ([0039]; See also Figure 3F in post filed art by inventors Png et al. Blood Adv. 2017;1(25):2348-2360, cited in the IDS filed 06/13/2024).
Before the effective filing date of the claimed invention, the generation of a scFv linked to a localizing domain was known in the art, as evidenced by Böldicke et al. (J. Cell. Mol. Med. Vol 11, No 1, 2007 pp. 54-70; cited in the IDS filed 6/13/2024). Böldicke et al. teaches targeting vectors comprising a nucleic acid sequence encoding a scFv ER intrabody comprising an ER retention signal where ER intrabodies could block the cell surface expression of oncogenically activated proteins (page 57; first paragraph, page 61; col. 1). However, Applicants are on record as stating that these prior art attempts to use intracellular antibodies targeted to the ER are not predictable. At page 9 of Applicants' remarks filed on 10/22/2018 and pages 8-9 of Applicants' remarks filed on 3/14/2019 for Inventors' Application 15/548,577 (cited in the IDS filed 6/13/2024, NPL #005 and #006), Applicants have previously asserted, "Böldicke states that " However, it seems to be not possible to predict if an antibody is fully active as an intrabody." (See page 60, right col., last sentence) Also, Böldicke cautions that "[C]ytoplasmic intrabodies often have folding and stability problems, resulting in low expression levels and limited half-life of antibody domains to the reduced environment [72]." (See, page 57, left col., last sentence bridging to the right col.) Böldicke clearly points to the unpredictability of the intrabody technology. Therefore, one skilled in the art would not have a reasonable expectation of success based on the teachings of Böldicke to readily envision a LD [localization domain]-linked target-binding molecule that functions according to the claims aside from those disclosed in the specification.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the CD7-binding target-binding molecule or CAR referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed encoded constructs; and, therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). The skilled artisan must be able to readily envisage the encompassed constructs which for claim 1 prevent fratricide of the immune cell in which they are expressed. For claim 17, there is a further functional requirement that introduction of the first and second encoding nucleic acids do not affect expansion or function of the engineered immune cell.
Therefore, only a method of producing an engineered immune cell, wherein the immune cell comprises the encoded CAR and target-binding molecule, both of which have a CD7-binding domain that is a scFv, and also for the target-binding molecule, wherein the localization domain has the sequence of SEQ ID NO:8, 9 or 10, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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 1-6, 8, 12-15 and 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-11 of U.S. Patent No. 11,679,132 B2 (‘132). Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim an engineered immune cell comprising a polynucleotide encoding a CAR comprising a scFv CD7-binding domain (comprising SEQ ID NO: 16 and 17 or 20 and 21), a transmembrane domain, 4-1BB costimulatory domain and CD3zeta signaling domain (claim 1 of ‘132 and instant claims 1, 3-6, 8, 13-15). Both claim a polynucleotide encoding a construct that downregulates endogenous CD7 surface expression comprising scFv anti-CD7 VH and VL or CDRs thereof linked to an ER retention signal (claims 3-5, 7-11 of ‘132 and instant claims 1, 2, 4-6, 13-15, 17 and 18), thereby inherently preventing fratricide of the engineered immune cell. SEQ ID NO: 16, 17, 20, 21 are respectively the same as instant SEQ ID NO:1, 2, 14, 15. Inherently the presence of the first and second polynucleotides would not have affected expansion or function of the engineered immune cell. The immune cell can be an T or natural killer (NK) cell (claim 2 of ‘132 and instant claim 12). It would have been obvious to produce the engineered immune cell by culturing the immune cell comprising the two polynucleotides so that the CAR was expressed because that would make the cell useful for immune cell therapy.
Claims 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-11 of U.S. Patent No. 10,550,183 B2 (‘183). Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim an engineered immune cell comprising a second polynucleotide encoding a CAR comprising a scFv CD7-binding domain (SEQ ID NO:1 and 2 or 14 and 15 or 16 and 17), a hinge and transmembrane domain (SEQ ID NO:10), 4-1BB costimulatory domain (SEQ ID NO:3) and CD3zeta signaling domain (SEQ ID NO:4; claim 1-5 of ‘183 and instant claims 1, 3-6, 8-11, 13-15). Both claim a first polynucleotide encoding a construct comprising scFv anti-CD7 VH and VL or CDRs thereof linked to an ER retention sequence (SEQ ID NO:8; claim 1 of ‘183 and instant claims 1, 2, 4-6, 13-15, 17 and 18), thereby inherently preventing fratricide of the engineered immune cell and the presence of the first and second polynucleotides would not have affected expansion or function of the engineered immune cell (instant claims 1 and 17). The immune cell is a T cell (claim 1 of ‘183 and instant claim 12). It would have been obvious to produce the engineered immune cell by culturing the immune cell comprising the two polynucleotides so that the CAR was expressed because that would make the cell useful for immune cell therapy.
Claims 1-8, 12-15 and 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-11 of U.S. Patent No. 11,440,958 B2 (‘958). Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim an engineered immune cell comprising a second polynucleotide encoding a CAR comprising a scFv CD7-binding domain (SEQ ID NO:1 and 2 or 14 and 15), 4-1BB costimulatory domain and CD3zeta signaling domain (claim 1-4 of ‘958 and instant claims 1, 3-6, 8, 13-15). Both claim a first polynucleotide encoding a construct comprising scFv anti-CD7 VH and VL of SEQ ID NO:1 and 2, linked to an ER retention sequence (SEQ ID NO:8, 9 or 10; claims 1-4 of ‘958 and instant claims 1, 2, 4-7, 13-15, 17 and 18), thereby inherently preventing fratricide of the engineered immune cell and the presence of the first and second polynucleotides would not have affected expansion or function of the engineered immune cell (instant claims 1 and 17). It would have been obvious wherein the immune cell was a T cell for CAR-T therapy and the polynucleotides were on different vectors to allow for different means of transduction into the cell (instant claims 12 and 18). It would have been obvious to produce the engineered immune cell by culturing the immune cell comprising the two polynucleotides so that the CAR was expressed because that would make the cell useful for immune cell therapy.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
WO 2016126213 is excepted as prior art under 102(b)(2)(a) because the only inventors on the publication are inventors of the instant invention and was made less than a year before the effective filing date of the claimed invention. The Applicant is the same.
Hanssens et al. (Med. Res. Rev. 42:306342, 2022) teaches different antibody-based antigen-binding domains of CARs (Fig. 4 I-III. There are advantages and disadvantages of each (Table 1), however, any antibody known in the prior art could have been encoded by the second nucleic acid of claim 1 as part of the CAR that specifically bound CD7.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
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 .
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.
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
Prosecution Insights