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 .
Claims Status
Claims 46-70 are pending and are examined on the merits.
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:
Specific deficiency - Sequences appearing in the drawings (Fig. 9) 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.
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.
Specification
The use of the term NANOBODY®, 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.
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.
Claims 46-70 are 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.
Claims 46-70 contain 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 “variable heavy chain-only immunoglobulins derived from camelids” (instant specification ¶0146) and, accordingly, the identification/description is indefinite.
Claim 51 is further rejected for making reference to a figure of the disclosure (“as shown in Fig. 9”). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim.” See MPEP 2173.05(s).
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 58-60 and 62 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 claims contain 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.
Scope of the claimed genus
Claims 58-60 and 62 are drawn to a method of treating CD72-positive malignant myeloid cells or multiple myeloma comprising administering immune cells expressing a CD72 CAR, and therefore require that the target cells express CD72.
State of the prior art
Nix et al. 2019 (Blood, 134, 1337.; IDS dated 07/05/2023) teaches proteomic analysis of surface antigens enriched in MLLr leukemia relative to non-MLLr B-ALL in order to identify novel targets for the MLLr subtype. Nix further teaches that CD72 was significantly enriched in the MLLr subtype vs other B-ALL subtypes, and further confirmed high expression of CD72 on DLBCL (diffuse large B cell lymphoma – a non-hodgkin lymphoma). Nix teaches that CAR T cells targeting CD72 effectively lysed B-ALL and DLBCL cells displaying a broad range of CD72 expression, whereas the same cells “had no activity versus CD72 negative cells”. The prior art, however, contains no mention of myeloid or multiple myeloma cells that express CD72 nor any treatment of multiple myeloma containing a CD72-directed binding agent.
Examples of the instant disclosure
Consistent with the prior art, the instant disclosure teaches CD72 CAR T killing of DLBCL and MLLr cells (Example 3). However, notably, there are no examples disclosed of CD72-positive multiple myeloma cells nor killing thereof with the CD72 CAR. In fact, the instant disclosure employs a multiple myeloma cell line as a CD72-negative control (¶0148).
Accordingly, one of ordinary skill in the art would be unable to envisage a method of treating malignant myeloid cells or multiple myeloma comprising administering the cells expressing the instantly claimed CD72 CAR.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 46, 54-58, 61-63, 65-66, and 68-70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nix et al. 2019 (Blood, 134, 1337.; IDS dated 07/05/2023), herein “Nix”, and as evidenced by the instant specification.
Regarding Claim 46, Nix teaches anti-CD72 nanobody clone “Nb.D4” (§ Results and Methods). As evidenced by the instant disclosure, anti-CD72 nanobody clone “D4” comprises CDRs of instant SEQ ID NOs: 44, 45, 46 (¶0151; Fig. 9; SEQ ID NO: 6).
Regarding Claims 54-57, 65-66 and 68-70, Nix teaches “nanobodies were incorporated into 2nd generation CAR constructs and transduced into normal donor CD8+ T-cells” (§ Results and Methods).
Further, regarding Claims 65-66, as evidenced by of the instant specification (¶0166; Pg. 37, § “Nucleic Acids and Vectors Encodings CARS), transduction is the process of delivering nucleic acids via viral vectors to genetically modify an effector cell, and therefore the “transduced” constructs of Nix necessarily contained a polynucleotide encoding the CAR in a viral vector.
Regarding Claims 58 and 61-63, Nix teaches a method of treating Mixed-lineage leukemia (MLLr) or DLBCL (a non-Hodgkin lymphoma) comprising administering 5x106 CD72(Nb.D4) CAR-T cells (i.e. a “plurality”) to tumor-bearing mice (§ Results and Methods; Fig 2).
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 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Nix et al. 2019 (Blood, 134, 1337.; IDS dated 07/05/2023), herein “Nix”, as applied to claim 46 above, and further in view of Kunz et al. 2017 (Biochimica et Biophysica Acta (BBA)-General Subjects, 1861(9), 2196-2205.; PTO-892), herein “Kunz”.
Nix does not teach that the anti-CD72 nanobody D4 further comprises framework mutations. This deficiency is cured by Kunz.
Kunz teaches protein engineering strategies to improve the thermal stability of nanobodies by introducing stabilizing amino acid variants/mutations (Abstract).
Kunz further teaches that combined mutations of Q1E and Q5V in particular have strong stabilizing effects (Fig. 4; § 3.3 “The mechanism of stabilization”). Kunz highlights that this pair of mutations has previously been demonstrated to improve solubility and thermostability in two other nanobodies, and suggest that said mutations may be of general benefit and both positions should be considered for general modifications in future nanobody phage-display vectors (Pg. 2203-2204; §4 “Discussion”).
It would have been obvious to one of ordinary skill in the art to modify the positions 1 and 5 of the D4 anti-CD72 nanobody of Kunz to comprise amino acids E at position 1 and V at position 5. The skilled artisan would have been motivated to substitute these two amino acids because Kunz teaches that this pair of mutations improves the thermostability of the resulting nanobody. There would have been a reasonable expectation of success because Kunz teaches that the Q1E and Q5V mutations provide a general benefit to the biophysical properties and have been shown effective in a variety of different nanobodies.
Claims 59-60 are rejected under 35 U.S.C. 103 as being unpatentable over Nix et al. 2019 (Blood, 134, 1337.; IDS dated 07/05/2023), herein “Nix”, as applied to claims 46, 54, 56, and 58 above, and further in view of Depil et al. 2020 (Nature reviews Drug discovery, 19(3), 185-199; PTO-892), herein “Depil”.
The teachings of Nix are summarized above.
Nix is silent on whether the CD72 CAR T cells are autologous or allogeneic. This deficiency is cured by Depil.
Depil teaches that use of patient-derived autologous cells for CAR T therapy “has resulted in outstanding clinical data to date”, and “autologous CAR-T cell therapy is associated with the absence of allogeneic reaction, and the engineered T cells can thus persist for a long time” (Pg. 185, ¶2). Depil teaches that autologous T cells present with a few disadvantages such as cost and delay to treatment owing to the ~3 week required production time (Pg. 185, ¶2).
Depil teaches allogeneic T Cells as alternative to autologous cells. Depil teaches that although allogeneic T cells present a greater risk of GvHD and host immune rejection, they present with many advantages such as being sourced in high quantities from healthy individuals (Pg. 185 § Allogeneic CAR T cell sources), and immediate availability of cryopreserved cells for patients in need (Pg. 186, ¶1). Depil teaches several recent approaches in mitigating the risks associated with allogeneic cells such as TRAC and MHC knockdown or use of γδ T Cells, many of which are in ongoing clinical trials (Table 2).
Owing to the advantages and disadvantages of each approach, it would have been obvious to one of ordinary skill in the art to employ either allogeneic or autologous CD72 CAR T cells in the method of treatment taught by Nix. The skilled artisan would have been motivated either by the greater persistence and lower risk of graft rejection offered by autologous cells or the lower cost and ready availability associated with off-the-shelf allogeneic cells. There would have been a reasonable expectation of success because both autologous and allogeneic approaches have yielded clinical successes.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Nix et al. 2019 (Blood, 134, 1337.; IDS dated 07/05/2023), herein “Nix”, as applied to claims 46, 54, and 65-66 above, and further in view of Xu et al. 2001 (Molecular therapy, 3(1), 97-104.; PTO-892), herein “Xu”.
The teachings of Nix are summarized above.
Nix is silent on whether the viral vector is a “self-inactivating lentiviral vector”. This deficiency is cured by Xu.
Xu teaches that self-inactivating (SIN) viral vectors are modified such that the vector is incapable of further replication upon infection of a target cell, thereby improving biosafety (§ Introduction). Xu further teaches SIN vectors are “regarded as the vectors of choice in human clinical trials” (§ Introduction).
It would have been obvious to one of ordinary skill in the art that the viral vector employed by Nix in generating the CD72(Nb.D4) CAR-T cells could be a self-inactivating vector. The skilled artisan would have been motivated to employ such a vector to ensure the virus is incapable of replication upon infection of the T cells, thereby improving safety. There would have been a reasonable expectation of success because such self-inactivating vectors are considered the vectors of choice for human clinical applications.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Claims 49, 50, and 51 are drawn to humanized D4 variants “H3”, “H10”, and “H24”, respectively, each comprising a discrete set of framework mutations relative to parental D4. As highlighted by the disclosed examples, the influence of any particular set of framework mutations on the ability of the anti-CD72 binders to function in the context of CAR T killing is unpredictable and must be determined empirically (Example 4; ¶0158).
For example, variants H3 and H10 has target killing efficacy “equivalent to parental llama-based CD72(NbD4) CAR” (¶0158), and H24 “displayed similar ability to degranulate comparable to parental NbD4” (¶0160), whereas variants H6 and H9 displayed “nearly 50% lower cell killing” (¶0158). Notably, despite the large disparity in target cell killing, H9 and H10 differed at only two positions within the framework region (Fig. 9, compare “D4-H9” with “D4-H10”).
Accordingly, Claims 49-51 are drawn to specific humanized variants of anti-CD72 clone D4 having unexpected properties that could not have been predicted a priori by one of ordinary skill in the art.
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
/GARY B NICKOL/Primary Examiner, Art Unit 1643