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 .
Election/Restriction
The two responses, both filed on 05/26/26 to the restriction requirement of 11/26/25 have been received. Without traverse, Applicant has elected:
in a first response, the Chimeric Antigen Receptor (CAR) comprising the amino acid sequence of SEO ID NO: 60 (as delineated in claims 10 and 37); and
in a second response, the Chimeric Antigen Receptor (CAR) comprising the amino acid sequence of SEO ID NO: 56 (as delineated in claims 11 and 38).
The election of two different species in two responses is not strictly in accordance with the restriction requirement to elect a single species. Nevertheless, the Examiner would proceed to examine the two species of SEQ ID NOs: 60 and 56. In addition, the Examiner rejoins the species of SEQ ID NO: 10 (recited in claims 10 and 37).
Status of Claims
Claims 1, 2, 6, 8, 10-12, 15-20, 22, 25, 27, 31, 35, 37 and 38 are pending.
Claim 2, 6, 8, 10-12, 15, 17, 20, 25, 27, 31, 35, 37 and 38 have been amended.
Claims 1, 2, 6, 8, 10-12, 15-20, 22, 25, 27, 31, 35, 37 and 38 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 09/14/2020 based on the provisional application 63078237 (filed 09/14/2020).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
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 – The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
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 incorporation by reference paragraph, 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.
In addition, this application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that the amino acid sequence of SEQ ID NO: 60 in paragraph [0295] for scFv heavy chain is not a sequence that has been disclosed in the Sequence Listing. Further, in paragraphs [0295] and [0440], another amino acid sequence consisting of 356 residues has also been assigned with the identifier of SEQ ID NO: 60 which matches with the sequence provided in the Sequence Listing for sequence number 60. Even further, it is noted that SEQ ID NOs: 90, 91, 92 provided in paragraphs [0131] and [0132] do not match those provided in the Sequence Listing.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and a statement that the substitute specification contains no new matter.
Claim Objections
Claims 10 and 31 are objected to because of the following informalities:
Claim 10 appears to contain a typographical error. The term “SEQ D NOs” should be “SEQ ID NOs” where an “I” is missing in “ID”.
Claim 31 recites the phrase “….wherein hinge region comprises….” It is suggested that the word “the” be inserted into the phrase such that the claim recites “wherein the hinge region comprises”.
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.
Claims 10, 31 and 35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 recites “an amino acid sequence of any one of SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, 57, and 60-92”. However, it is noted that SEQ ID NOs: 84-89 are nucleotide sequences ranging from 30 to 1179 bases long. Therefore, it is unclear whether claim 10 is directed to amino acid sequences or nucleotide sequences.
It is unclear what the claim refers to when
Claim 31 contains the trademark/trade name “nanobody" in line 3. 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 the antigen-binding domain in the CAR and, accordingly, the identification/description is indefinite.
Claim 35 recites the phrase “The method of any one of claims 19-34….” The claims is indefinite because claims 21, 23, 24, 26, 28-30 and 32-34 are canceled claims. The metes-and-bounds of claim 35 are unclear because it is unclear how claim 35 limits a method of a cancelled claim.
Claim Rejections 35 U.S.C.112(a) – (First)
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 10, 11, 37 and 38 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.
In the instant case, the following genus have been noted:-
claims 10 and 37 are inclusive of a genus of isolated nucleic acid molecule encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the CAR comprises an amino acid sequence having 95-99% identity to any one of SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, 57, and 60-92, which includes mutations of up to 5% in the CDR regions responsible for providing the function of binding to CD33; and
claims 11 and 38 are inclusive of a genus isolated nucleic acid molecule encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the nucleic acid molecule comprises a nucleotide sequence with 95-99% identity to any one of SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56, which includes mutations of up to 5% in the CDR regions responsible for providing the function of binding to CD33.
However, the written description in this case only sets forth sixteen species disclosed in paragraph [360] (Pg 145 of instant specification) which teaches that CAR constructs generated are shown in the amino acid sequences SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, and 57 and are encoded by the nucleic acid sequences shown in SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56. In addition, the specification in Table 4 teaches sequences of CAR constructs and controls (paragraph [0440] Pg 154-159) which sets forth twelve constructs. Of these, four constructs have been described in paragraph [0360] namely SEQ ID NOs: 13 (CD33-CAR4), 19 (CD33-CAR3), 22 (CD33-CAR1) and 29 (CD33-CAR2), while SEQ ID NOs: 60 (CD33-CAR5), 90 (CD33-CAR6), 91 (CD33-CAR7), 92 (CD33-CAR8), 94 (CD33-CAR9), 95 (CD33-CAR10), 96 (CD33-CAR11) and 97 (CD33-CAR12) are different constructs. Therefore, at most twenty-four CARs were disclosed in the specification wherein the CAR comprises a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain. The specification does not disclose, and the art does not teach, the genus of isolated nucleic acid molecule encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain as broadly encompassed in the claims.
As is well-known in the antibody art at the time of filing, the specificity of an antibody is dependent upon the six CDR regions and different combinations of CDR sequences greatly alter antigen binding. It is well established that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (reviewed in Sela-Culang et al. Frontiers in immunology 4 (2013): 302). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences, 1982, 79:1979-1983). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Therefore, there is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of a scFv to bind to CD28 or a Fab to bind to PD-L1 comprising mutations in any of the six CDR regions, or comprising mixing and matching a known set of three CDRs with an undefined set of three CDRs, which is also a form of introducing mutations into the CDR regions.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of species antigen binding domains that encompass the genus nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are 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.
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of twenty-four CARs comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain found in the specification is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, 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 isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. 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).
Claim Rejections 35 U.S.C.112(a) – (Second)
Claims 10, 11, 37 and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (i) isolated nucleic acid molecules encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the CAR comprises an amino acid sequence of any one of SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 90-92; or (ii) isolated nucleic acid molecules encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the nucleic acid molecule comprises a nucleotide sequence selected from any one of SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56; does not reasonably provide enablement for (i) isolated nucleic acid molecules encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the CAR comprises an amino acid sequence having 95-99% identity to any one of SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 90-92; or (ii) isolated nucleic acid molecules encoding a CAR comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the nucleic acid molecule comprises a nucleotide sequence with 95-99% identity to any one of SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The nature of the invention
Claims 10 and 37 are drawn to CARs comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the CAR comprises an amino acid sequence having 95-99% identity to any one of SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, 57, and 60-92, which includes up to 5% mutations in and around the CDR sequences responsible for providing the function of binding to CD33. Claims 11 and 38 are drawn to CARs comprising a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the nucleic acid molecule comprises a nucleotide sequence with 95-99% identity to any one of SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56, which includes mutations of up to 5% in the CDR regions responsible for providing the function of binding to CD33.
The breadth of the claims
The claims are broad in that they encompass mutant CDRs with up to 5% mutations in the CDRs of the CD33 binding domain that would retain the function of binding to the target antigen.
The amount of direction provided by the inventor/the existence of working examples
The specification discloses in paragraph [360] (Pg 145 of instant specification) sixteen generated CAR constructs as shown by amino acid sequences SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, and 57 that are encoded by the nucleic acid sequences shown in SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56. In addition, the specification in Table 4 teaches sequences of CAR constructs and controls (paragraph [0440] Pg 154-159) which sets forth twelve constructs. Of these, four constructs have been described in paragraph [0360] namely SEQ ID NOs: 13 (CD33-CAR4), 19 (CD33-CAR3), 22 (CD33-CAR1) and 29 (CD33-CAR2), while SEQ ID NOs: 60 (CD33-CAR5), 90 (CD33-CAR6), 91 (CD33-CAR7), 92 (CD33-CAR8), 94 (CD33-CAR9), 95 (CD33-CAR10), 96 (CD33-CAR11) and 97 (CD33-CAR12) are different constructs. Therefore, a total of only twenty-four CAR constructs comprising CD-33 binding domains were disclosed.
Therefore, the disclosure does not discuss, or demonstrate through working examples, any novel mutants of the CARs, that retain the instant claimed functionalities.
The state of the art/the level of predictability in the art
The state of the art teaches that with regards to changes in the amino acid residues on binding domains, it is especially important to disclose which residues are permissive to mutation. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982, see Abstract). Further, an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Not knowing and absent further experimentation, which modifications can retain antigen binding function and which cannot, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict or otherwise envisage all possible mutations of up to 5% in the CDR regions of the CAR comprising the amino acid sequences of SEQ ID NOs: 10, 13, 16, 19, 22, 25, 29, 33, 36, 39, 42, 45, 48, 51, 54, 57 60 and 90-92; or possible mutations of up to 5% in the CDR regions of the CAR comprising the nucleotide sequences of SEQ ID NOs: 9, 12, 15, 18, 21, 24, 28, 32, 35, 38, 41, 44, 47, 50, 53, and 56, that would retain the binding function to CD33. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to create and function test all possible mutations on the CD33 binding domain for retention of functional activity.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. This is because the art teaches that it is unpredictable whether or not CDR variants of known antibodies or binding domains will function as such, and the specification does not provide direction on which constructs below 100% identity have function, or do not have function, as claimed in order to perform the method as claimed. In other words, the specification does nothing to ameliorate these concerns over the breadth of the claims rejected above with respect to functional variants, therefore, one would be burdened with undue experimentation to make or use the products of instant claims as broadly as they are currently claimed.
Enablement can be met by amending the claims to recite the CAR amino acid sequences and nucleotide sequences without any percentage identity variations.
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 1, 2, 6, 8, 10, 12, 15-20, 22, 25, 27, 31, 35 and 37 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Mukherjee et al. (WO2019046285A1 Date Published 2019-03-07).
Mukherjee et al. teaches compositions and methods relating to agents that target a lineage-specific cell-surface antigen and a population of hematopoietic cells that are deficient in the lineage-specific cell-surface antigen for immunotherapy of hematological malignancies (Abstract). They teach nucleic acid sequences of CD33-targeted chimeric antigen receptors (CAR) for T-cell therapy, wherein the CAR can comprise a leader peptide signal, a CD33 scFv, a hinge, transmembrane regions of the CD28 molecule, an intracellular domain of CD28, and a signaling domain of TCR-ζ molecule (Pg. 74 lines 1-7 and Figure 7B). They also teach in Figure 7A, CD33-binding CAR constructs that comprise a co-stimulatory domain (see below for Figures 7A and 7B as taught by Mukherjee et al.).
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Mukherjee et al. teaches that nucleic acids encoding the chimeric receptors can be cloned into a suitable viral expression vector that is in operable linkage to a suitable promoter, including the SFFV promoter and EF1alpha promoter (Pg 41 lines 17-19 and lines 30-32). They teach in Table 3 the construct named CART1 (SEQ ID NO: 20). Alignment of CART1 SEQ ID NO: 20 of Mukherjee et al. with instant SEQ ID NO: 10 shows that they are fully matched at 100% identity (see Alignment 1 below). Therefore, Mukherjee et al. teaches instant SEQ ID NO: 10. They also teach in Example 4 that CART1 is a CD33 binding CAR that was generated using convention recombinant DNA technologies and inserted into a pHIV-Zsgreen vector where the vector containing the CAR was used to generate lentiviral particles, which were used to transduce T cells and NK (Example 4 Pg 82 lines 8-15). They further teach that primary T cell populations (CD4+, CD8+, or CD4+/CD8+ cells) isolated from PMBCs obtained from donors by FACS were transduced with a lentiviral vector containing CART1 (Figure 13A and 13B and Pg 83 lines 26-31). In addition, they teach immune cells expressing CARs can be administered in a pharmaceutically acceptable carrier or excipient as a pharmaceutical composition (Pg 69 lines 22-24).
Alignment 1: Alignment of amino acid sequence of instant SEQ ID NO: 10 (top) with of SEQ ID NO: 20 of Mukherjee et al. (bottom)
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Mukherjee et al. teaches a method of treating a hematopoietic malignancy, comprising administering to a subject in need thereof: (i) an effective amount of an agent targeting CD33, wherein the agent comprises an antigen-binding fragment that binds CD33, and (ii) a population of hematopoietic cells that are genetically engineered to comprise mature transcript of CD33 having mutated or deficient exon 2 (claim 17); wherein the hematopoietic cells are engineered by CRISPR-Cas9 (claim 18); or wherein the genetically engineered hematopoietic cells are prepared by editing the endogenous gene coding for CD33 to result in loss of exon 2 from the mature transcript of CD33 (claim 19). They teach that subjects were infused with CD33 depleted hematopoietic stem cells (HSCs) (Pg 80 line 27).
Mukherjee et al. teaches the method of claim 17, wherein the subject has Hodgkin's lymphoma, non- Hodgkin's lymphoma, leukemia, and/or multiple myeloma (claim 27). They teach the method of claim 17, wherein the subject has leukemia, which is acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia (claim 28). They teach in Figures 11A and 11B that NK92 cells expressing chimeric receptor CART1 induced a substantial amount of cell death of target K562 cells at each of the assessed cell ratios (Example 4 Pg 83 lines 12-14). They further teach that K562 cells are a human chronic myelogenous leukemia cell line that are CD33+ (Example 4 Pg 82 lines 33-34).
Therefore, the teachings of Mukherjee et al. anticipate instant claims 1, 2, 6, 8, 10, 12, 15-20, 22, 25, 27, 31 and 37.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, 6, 8, 10-12, 15-20, 22, 25, 27, 31, 35, 37, and 38 are rejected under 35 U.S.C. 103(a) as being unpatentable over Mukherjee et al. (WO2019046285A1 Date Published 2019-03-07) as applied to claims 1, 2, 6, 8, 10, 12, 15-20, 22, 25, 27, 31, 35 and 37 above, and further in view of Orentas et al. (US20180280438A1 Date Published 2018-10-04).
The teachings of Mukherjee et al. have been described in the 102 rejection above.
Mukherjee et al. does not specifically teach the isolated nucleic acid molecule of instant claim 1, wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 56 .
However, these deficiencies are made up in the teachings of Orentas et al.
Orentas et al. teaches chimeric antigen receptors containing CD33 antigen binding domains, nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions relating to the chimeric antigen receptors, methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells (Abstract). They teach the nucleic acid sequence encoding a CAR comprises the nucleic acid sequence of SEQ ID NO: 17 (LTG 1906 EF1a-VH-4 CD33-CD8 TM-41BB-CD3 zeta nucleic acid sequence (paragraph [0047] and FIG. 2B). Alignment of the CAR nucleic acid sequence of SEQ ID NO: 17 of Orentas et al. with instant SEQ ID NO: 56 shows that they have 98.1% identity (see Alignment 2 below).
Alignment 2: Alignment of nucleic acid sequence of instant SEQ ID NO: 56 (top) with of SEQ ID NO: 17 of Orentas et al. (bottom)
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a CD33 binding domain, a transmembrane domain, and an intracellular signaling domain as set forth in SEQ ID NO: 20 as taught by Mukherjee et al. and substituting this with the nucleic acid sequence encoding a CD33 binding CAR comprising the nucleic acid sequence of SEQ ID NO: 17 as taught by Orentas et al., which also comprises a CD8 transmembrane and a CD3ζ intracellular signaling domain, and which has 98.1% identity to instant SEQ ID NO: 56 to make a CAR that specifically binds to CD33, because both the CARs have equivalent components which would therefore function in a predictable manner to yield results that are expected by a person of ordinary skill in the art. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a hematopoietic malignancy, comprising administering to a subject in need thereof an effective amount of an agent targeting CD33, wherein the agent is an immune cell expressing a chimeric receptor (CAR), wherein the CAR comprises: an antigen-binding domain that binds CD33 comprising a heavy chain variable region and/or a light chain variable region; a transmembrane domain comprising a transmembrane domain of a protein selected from CD8a or CD28; and an intracellular signaling domain comprising a functional signaling domain of CD3ζ as taught by Mukherjee et al., and substituting the CAR of Mukherjee et al. with the CD33-binding CAR which also comprises a CD8 transmembrane and a CD3ζ intracellular signaling domain that is encoded by the nucleotide sequence of SEQ ID NO: 17 as taught by Orentas et al., because both the CARs have equivalent components which would therefore function in a predictable manner for treating a hematopoietic malignancy to yield results that are expected by a person of ordinary skill in the art. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Allowable Subject Matter
The amino acid sequence of SEQ ID NO: 60 is free of prior art.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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