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
Claim status
Claims 1-14 are pending
Claims 1-14 are under examination
Information Disclosure Statement
No information disclosure statement (IDS) has been submitted.
Furthermore, Applicant is reminded that 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.
Objection to Drawings and Specification
Sequence Compliance
First, Figure 8 (G), Figure 9 (A-D) and Figure 14 (A & B) of the Specification do not conform to sequence rules, requiring the use of “SEQ ID NO:” (37 CFR 1.821-1.825).
Second, Table 1 (p.26), Table 2 (p. 28), Tables 3 & 4, (p. 29), Table 5 (p. 30), Tables 8 & 9 (pgs. 32-33) of the Specification do not conform to sequence rules, requiring the use of “SEQ ID NO:” (37 CFR 1.821-1.825).
Where the description or claims of a patent application discuss a sequence that is set forth in the “Sequence Listing” in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. 37 CFR 1.821 (d).
The applicant is reminded that the specification must be amended in order to comply with regulations cited above. All references to sequences in claims and specification should be referred to as “SEQ ID NO:1”, for example. To avoid all doubts of the examiner and to ensure correct interpretation of the claims and specification, the identification of sequences with proper sequence identifiers is required.
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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, 7-9 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grupp et al., (N Engl J Med, 2013, 368:1509-1518, published 4/18/2013).
With respect to claims 1, 8 and 9, Grupp teaches a method of inhibiting a CD19+ B cell neoplasm in a human subject comprising administering a therapeutically effective amount of CAR modified T cells (i.e., CTL019 T cells) which recognizes the ectodomain of the CD19 isoform (p. 1510-1511, Case Reports).
In regard to claim 2, Grupp teaches the B cell neoplasm is a pre-B cell acute lymphoblastic leukemia (ALL) (p. 1510, Case Reports).
In regard to claim 7, Grupp teaches further administrating chemotherapeutics etoposide and cyclophosphamide (p. 1512, Patient 2).
In regard to claim 14, Grupp teaches the step of determining CD19 expression of the full-length wild-type isoform by the B cell neoplasm prior to the treatment of the subject (p. 1516, Fig. 3A).
Accordingly, Grupp anticipates instant claims.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Tyner et al., (US2013/0131139, filed 11/17/2011, filed 5/23/2013), as evidenced by Borowitz et a., (Blood, 1993, 82:1086-1091).
Tyner teaches a method of inhibiting a B cell neoplasm in a human subject comprising administering a therapeutically effective amount of a Src family kinase inhibitor ([0004, 0006, 0056, 0089, 0132, 0137], Fig. 5).
In regard to the type of B cell neoplasms as per claims 1 and 2, Tyner teaches that the cancer patients comprise a t(1;19) karyotype for B cell acute lymphoblastic leukemia (B-ALL) ([0148], Fig. 5E). Importantly, Borowitz evidences that this karyotype of B-ALL express CD19 (Abstract and Table 1 of Borowitz).
In regard to claims 4-6, Tyner teaches the Src family kinase inhibitor is the Lyn inhibitor dasatinib (Fig. 5E).
In regard to claim 7, Tyner teaches the treatment with the Lyn kinase inhibitor dasatinib is combined with a chemotherapeutic siRNA against ROR1 (Example 1, [0244]).
However, Tyner is silent to a preferred embodiment of a method for treating a subject in vivo having a CD19+ B cell neoplasm with the Lyn kinase inhibitor dasatinib.
Nevertheless, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to practice said method to treat B cell neoplasms in vivo because each of the individual elements of the instant claims are independently presented by Tyner as embodiments and are taught that they can be combined in various embodiments; therefore a combination of all the elements into a single embodiment would be apparent to an artisan skilled in cancer therapy in light of the Supreme Court’s KSR decision (see MPEP 2143 Exemplary Rationale (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of filing of the invention. Each of the elements (inhibition of B-ALL by dasatinib, in vivo animal models and human clinical trials, delivery methods and formulations) are taught by Tyner and further they are taught in various combinations and are shown to be used in a method for treating B-ALL with dasatinib in vivo. It would be therefore predictably obvious to use a combination of these elements in said method.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 3, 10-11, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Tyner et al., (US2013/0131139) as evidenced by Borowitz et a., (Blood, 1993, 82:1086-1091), in view of Grupp et al., (N Engl J Med, 2013, 368:1509-1518, published 4/18/2013,) as evidenced by NCBI Reference Sequence NM_001385732, first published 1991)
As discussed previously, Tyner suggests a method of inhibiting a CD19+ B cell neoplasm in a human subject comprising administering a therapeutically effective amount of a Src family kinase inhibitor.
However, although Tyner teaches that anti-CD19 CAR T cell (i.e., CART19) therapy is used to treat the taught B cell neoplasms [0271], they are silent with respect treating a CD19+ B cell neoplasm with a Src family kinase inhibitor after CART19 therapy.
With respect to claim 3, Grupp teaches a method of inhibiting a CD19+ B cell neoplasm in a human subject comprising administering a therapeutically effective amount of CART19 cells (p. 1510-1511, Case Reports). Importantly, Grupp teaches these patients’ relapse with tumors that no longer express wild-type CD19 (Abstract, p. 1516, Emergence of CD19 escape variant).
In regard to claims 10 and 11, specifically in regard to the relapsed tumors that comprise a CD19 isoform not comprising exon 2, such that the relapsed tumor do not substantially express wild-type CD19, Grupp provides a molecular analysis of the patient’s relapsed B cell neoplasm (alias CHOP-101 cells) (see Figures S1 and S3B of Supplemental methods), wherein said relapsed neoplastic CHOP-101 cells after anti-CD19 CART therapy are no longer recognized by a CD19 antibody that binds the extracellular domain of human CD19 comprising the region encoded by exon 2. Importantly, the relapsed CHOP-101 cells of Grupp appear to be identical to the CHOP-101 cells sequenced by instant Applications, which exhibit reduced exon 2 expression due to exon skipping (see p. 37, Fig. 8 of Applicant’s disclosure). Furthermore, the Dexon2 isoform of human CD19 was well known in the art at the time of filing as evidenced by NCBI Reference Sequence NM_001385732, first published 1991 (see splice site between exons 1 and 3 at nucleotides g118/g119). Thus, the CHOP-101 cells after CART19 therapy of Grupp naturally do not express the wild-type CD19 isoform and alternatively express a splice isoform comprising a deletion in exon 2.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to practice the method of inhibiting a B cell neoplasm with a Src kinase inhibitor as taught by Tyner and to do so in a relapsed patient having undergone CART19 therapy, wherein the patient comprises relapsed CHOP-101 cells as taught by Grupp with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, Grupp teaches that the emergence of tumor cells that no longer express CD19 indicates a need to target other molecules in these patients (Abstract). Among the other molecules to target in relapse patients, Tyner teaches that tyrosine kinase inhibitors would have been obvious in these patients because they block pre-BCR signaling required for tumor survival ([0014, 0020], see Fig. 5F of Tyner). Furthermore, Tyner teaches and that most t(1:19) ALL patients exhibit a high rate of relapse and the current cell-based salvage therapies are not effective, therefore “these patients may benefit with the addition of therapies to improve outcomes” [0135], to wit, SFK inhibitor/anti-ROR1 chemotherapy.
In regard to claim 14, Grupp teaches the step of determining CD19 expression by the B cell neoplasm both prior and after treatment of the subject in order to measure the effectiveness of the treatment with regard to CD19+B cell aplasia, as well as the emergence of CD19 escape variants (p. 1516, Fig. 3A/B, and Fig. S3B). This, step would have been obvious to include in the method of Tyner in view of Grupp so as characterize the reasons for relapse in the CART19 relapse patient’s to be treated. As stated supra, Grupp teaches that the emergence of tumor cells that no longer express CD19 indicates a need to target other molecules in these patients, such as SFKs/ROR1 of Tyner.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
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 10-13 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.
Claims 10-13 encompass methods of inhibiting a B-cell neoplasm comprising anti-CD19 chimeric antigen receptor (CAR) modified T (CART19) cells that recognize the ectodomain of a CD19 mutant comprising a deletion in exons 2, 5, and/or 6. Specifically, Applicant’s claimed method encompasses a genus of CART cells that that bind seven (7) types of CD19 antigens: (1) a CD19 antigen comprising an exon 2 deletion, which corresponds to the N-terminal half of the ectodomain region (see “CD19ex2” of Applicant’s Figure 12A below); (2) a CD19 antigen comprising an exon 5 deletion, which corresponds to the transmembrane domain region (see “CD19ex5-6” of Applicant’s Figure 12A below); (3) a CD19 antigen comprising an exon 6 deletion, which corresponds to the juxtamembrane cytoplasmic region (see “CD19ex5-6” of Applicant’s Figure 12A below); (4) a CD19 antigen comprising an exon 2/5 deletion, which corresponds to the regions identified supra; (5) a CD19 antigen comprising an exon 2/6 deletion, which corresponds to the regions identified supra; (6) a CD19 antigen comprising an exon 5/6 deletion, which corresponds to the regions identified; (7) a CD19 antigen comprising an exon 2/5/6 deletion, which corresponds to the regions identified supra.
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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.
ACTUAL REDUCTION TO PRACTICE
In regard to claims 10-13 encompassing a method of inhibiting a B-cell neoplasm comprising a genus of CART19 cells that recognize the ectodomain of a CD19 mutant comprising deletion in exons 2, 5, and/or 6, the specification describes no such CART19 cells.
Exon 2 deletion
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in this exon. To the contrary, Applicant discloses that the epitope recognized by the conventional CART19 cells used in instant Applicant is encoded by exons 1 and 2 of CD19 mRNA (p. lines 13-14). Thus, it appears that Applicant was NOT in possession of CART19 cells that would recognized a B-cell neoplasm comprising an exon 2 deletion mutant of CD19. This lack of written description is supported by Applicant’s working example in Figure 13, wherein Nalm-6 human leukemia cell line is transfected with CD19 isoforms to test responsiveness to CART19 cell therapy. As shown in Figure 13G, the parental CD19 negative Nalm cells with empty vector, or with vectors encoding the exon 2 deletion of CD19 are not inhibited by CART19. Only Nalm cells expressing the full-length CD19 (triangle symbols) are inhibited by CART19 cell therapy. Thus, Applicant’s disclosure provides no working examples of CART19 cells that would not recognized a B-cell neoplasm comprising an exon 2 deletion mutant of CD19.
Exon 5/6 deletion
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in these exons. Furthermore, Applicant’s Figure 13G also demonstrates that vectors encoding the exon 5/6 deletion of CD19 (circular symbols) are also not inhibited by CART19. Thus, Applicant’s disclosure lacks support for CART19 cells would recognized a B-cell neoplasm comprising an exon 5/6 deletion mutant of CD19.
Exon 2/5/6 deletion
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in these exons. As stated supra, Applicant’s Figure 13G supports that CART19 cells would not recognized a B-cell neoplasm comprising a combined an exon 2/5/6 deletion mutant of CD19.
Overall, the totality of evidenced indicates that neither the specification nor the prior art allow one skilled in the art to envision the structure of other antibodies that can be used in a CART19 cell to inhibit the B-cell neoplasms as claimed.
DISCLOSURE OF STRUCTURE
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in these exons.
Furthermore, Applicant has provided limited number of CD19 antibodies that could be used to make a CART19 cell that would recognize a B-cell neoplasm expressing a mutant CD19 isoform (see Table 7 of disclosure). For example, Figure 2A of Applicant’s disclosure demonstrates that the anti-CD19 antibody FMC63 does NOT recognize B-cell neoplasms comprising exon 2, 5, and/or 6 deletions (see negative FACs signals in CHOP101-R, CHOP105R2, and CHOP107R cells). In fact, the only antibody Applicant disclosed that could possibly recognized the CD19 extracellular domains in exon 2 and exon 5/6 deletions via FACS is a GeneTex antibody 5F3 (p. 23, 3rd para., see Fig. 6B, bottom panel). However, Applicant has provided no description of which CD19 mutant the anti-CD19 5F3 antibody binds or where in CD19 is the epitope for this monoclonal antibody, nor evidence that the immunoglobulin antigen binding domains of this antibody can be predictably incorporated into a CART cell to inhibit a B-cell neoplasm.
Certainly, with the help of a computer, a skilled artisan could identify the appropriate CD19 antigens to be used for generating an immunoglobulin gene to be used in the CART19 cells. Furthermore, immunization and screening steps could identify an immunoglobulin domain that binds the claimed genus of CD19 isoforms. However, neither the specification nor the art indicate a relationship between the structure of the claimed genus of CART19 cells (and immunoglobulin domains contained therein) and the ability to bind and inhibit B-cell neoplasms comprising the various CD19 mutant isoforms as claimed.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, Applicant provides no example of a CART19 cell that binds and inhibits a B-cell neoplasm comprising a deletion in these exons and a limited number of antibodies that can be used in a CART19 cell are provided. Accordingly, if the skilled artisan sought to generate the claimed genus of CART19 cells, they would first need to know which immunoglobulin gene could be chosen for the CAR and still be able to predictably produce a functional CD19 binding domain. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of CART19 cells beyond the antibodies described in the specification.
The breadth of the claims encompass a genus of CART19 cells comprising any amino acid in any immunoglobulin domain of the overexpressed CAR gene. The present specification provides no guidance nor description to any rational in choosing the CART19 cells that are claimed, therefore the skilled artisan would not know what rational approach to take to make modifications with any predictable outcome on CD19 antigen binding function. 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 CART19 cells related to those comprising these individual species. 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, 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 making the claimed invention is not well established. Although the screening of antigens is routine and conventional, one of skill in the art would neither expect nor predict the appropriate functioning of the CART cells to inhibit a B-cell neoplasm according to the genus of CART19 cells as broadly as is claimed. A single antigen can generate over a 1000 antibodies, all with different amino acid sequences as evidenced by Edwards et al., (JMB, 2003, 334:103-118). Furthermore, even a single amino acid change in the same antigen can dramatically affect antibody recognition and binding (Liang et al., (IJMS, 2010, 11:2962-2975). Applicant has claimed a genus of CART19 cells, yet the specification has not identified a single CART19 cell to be used and only discloses a very specific monoclonal CD19 antibody (i.e., the proprietary GeneTex 5F3) that could possibly used in a CART19 cell to bind the claimed CD19 antigens. Yet, even in this instance the description of a CART19 that expresses this potential antigen binding domain is lacking and it would be unpredictable to make such a CART19 cell. For example, Krug et al., (Cancer Immuno Immunother, 2015, 64:1623-1635) evidence that just because an antibody’s antigen binding domain is known, making a CART cell comprising said antigen binding domain is unpredictable base not only on the scFv used (p. 1627, Results, col 2), but also the Fc constant domains used (p. 1631, Discussion, col 2), and because of different folding requirements in the CAR that were not part of the original antibody (p. 1632, Discussion, col 1). Because Applicant has no manner a priori to predict which antigen binding domain can be modified and used to make a functioning CART19 cell, the genus of CART cells claimed by Applicant cannot be predictably made or used by the ordinary artisan; and one skilled in the art cannot envision the structure of other antibodies to do so.
Not knowing, absent further experimentation and screening, which modifications function and which do not, when, as set forth above, even a single change of an antigen can unpredictably affect structure and function of the antibody, leads to one having no predictability or expectation of success for the function of any given chimeric antigen receptor. Such random experimentation to identify at a later time what structure or variant or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation. Furthermore, functionally defined genus claims (i.e., a CAR-modified T cell which “recognizes the ectodomain of said CD19 isoform”) 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
Therefore, the examiner concludes that there is insufficient written description of the instantly claimed genus of CART19 cells. Specifically, there is limited description of the structure-function relationship between the claimed genus of CART19 cells and their ability to bind and inhibit a B-cell neoplasm that expresses an exon 2, 5, and/or 6 deletion of CD19, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the nucleic acids encompassed by the claimed genus.
Enablement/ Scope of Enablement
Claims 10-13 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 enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Furthermore, while claims 10 and 11 are enabled for using a SFK inhibitor and/or CD20/CD22 CART cell to inhibit a B-cell neoplasm that expresses a CD19 isoform comprising a deletion in exons 2, 5, and/or 6, does not provide enablement for a CD19 CART cell.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
SCOPE OF THE INVENTION
Claims 10-13 encompass methods of inhibiting a B-cell neoplasm comprising a genus of chimeric antigen receptor (CAR) modified T (CART) cells that recognize the ectodomain of a CD19 mutant comprising a deletion in exons 2, 5, and/or 6. Specifically, Applicant’s method encompasses a genus of CART cells that that bind seven (7) types of CD19 antigens: (1) a CD19 antigen comprising an exon 2 deletion, which corresponds to the N-terminal half of the ectodomain region (see “CD19ex2” of Applicant’s Figure 12A below); (2) a CD19 antigen comprising an exon 5 deletion, which corresponds to the transmembrane domain region (see “CD19ex5-6” of Applicant’s Figure 12A below); (3) a CD19 antigen comprising an exon 6 deletion, which corresponds to the juxtamembrane cytoplasmic region (see “CD19ex5-6” of Applicant’s Figure 12A below); (4) a CD19 antigen comprising an exon 2/5 deletion, which corresponds to the regions identified supra; (5) a CD19 antigen comprising an exon 2/6 deletion, which corresponds to the regions identified supra; (6) a CD19 antigen comprising an exon 5/6 deletion, which corresponds to the regions identified; (7) a CD19 antigen comprising an exon 2/5/6 deletion, which corresponds to the regions identified supra.
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GUIDANCE & WORKING EXAMPLES
In regard to claims 110-13 encompassing a method of inhibiting a B-cell neoplasm comprising anti-CD19 CAR modified T cells that recognize the ectodomain of a CD19 mutant comprising deletion in exons 2, 5, and/or 6, while the specification discloses no such CART cells.
Exon 2 deletion
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in this exon. To the contrary, Applicant discloses that the epitope recognized by the conventional CART19 cells used in instant Applicant is encoded by exons 1 and 2 of CD19 mRNA (p. lines 13-14). Thus, it appears that Applicant was NOT in possession of CART19 cells that would recognized a B-cell neoplasm comprising an exon 2 deletion mutant of CD19. This lack of enablement is supported by Applicant’s working example in Figure 13, wherein Nalm-6 human leukemia cell line is transfected with CD19 isoforms to test responsiveness to CART19 cell therapy. As shown in Figure 13G, the parental CD19 negative Nalm cells with empty vector, or with vectors encoding the exon 2 deletion of CD19 are not inhibited by CART19. Only Nalm cells expressing the full-length CD19 (triangle symbols) are inhibited by CART19 cell therapy. Thus, Applicant’s disclosure provides no working examples of CART19 cells that would not recognized a B-cell neoplasm comprising an exon 2 deletion mutant of CD19.
Exon 5/6 deletion
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in these exons. Furthermore, Applicant’s Figure 13G also demonstrates that vectors encoding the exon 5/6 deletion of CD19 (circular symbols) are also not inhibited by CART19. Thus, Applicant’s disclosure lacks support for CART19 cells would recognized a B-cell neoplasm comprising an exon 5/6 deletion mutant of CD19. As a second matter with respect to enablement of these particular CD19 mutants, it appears the extracellular region is unchanged in CD19 molecules comprising a deletion of exons 5 and/or 6, yet in light of Applicant’s Fig. 13G, CART19 cells do not inhibit this isoform. Thus, the CD19 molecule lacking exons 5 and/or 6 must escape CART19 detection in some manner (e.g., they no longer comprises a transmembrane region to anchor it to the cell surface). Thus, how would a CAR recognize the B cell lacking surface expression of a CD19 molecule that is not tethered to the surface of the cell’s plasma membrane or is only expressed within the cell as evidenced by Applicant’s western blotting (e.g. Applicant’s Fig. 12B). Note: this issue is also germane to the CD19 molecule lacking exons 2, 5, and 6, discussed below.
Exon 2/5/6 deletion
Applicant provides no example of a CART19 cell that binds a B-cell neoplasm comprising a deletion in these exons. As stated supra, Applicant’s Figure 13G supports that CART19 cells would not recognized a B-cell neoplasm comprising a combined an exon 2/5/6 deletion mutant of CD19.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although the screening of antigens is routine and conventional, one of skill in the art would neither expect nor predict the appropriate functioning of the CART cells to inhibit a B-cell neoplasm according to the genus of CART19 cells as claimed. A single antigen can generate over a 1000 antibodies, all with different amino acid sequences as evidenced by Edwards et al., (JMB, 2003, 334:103-118). Furthermore, even a single amino acid change in the same antigen can dramatically affect antibody recognition and binding (Liang et al., (IJMS, 2010, 11:2962-2975). Applicant has claimed a genus of CART19 cells, yet the specification has not identified a single CART19 cell to be used and only discloses a very specific monoclonal CD19 antibody (i.e., the proprietary GeneTex 5F3) that could possibly be used in a CART19 cell to bind the claimed CD19 antigens. Yet, even in this instance the enablement of a CART19 that expresses this potential antigen binding domain is lacking and it would be unpredictable to make such a CART19 cell. For example, Krug et al., (Cancer Immuno Immunother, 2015, 64:1623-1635) evidence that just because an antibody’s antigen binding domain is known, making a CART cell comprising said antigen binding domain is unpredictable base not only on the scFv used (p. 1627, Results, col 2), but also the Fc constant domains used (p. 1631, Discussion, col 2), and because of different folding requirements in the CAR that were not part of the original antibody (p. 1632, Discussion, col 1). Because Applicant has no manner a priori to predict which antigen binding domain can be modified and used to make a functioning CART19 cell, the genus of CART cells claimed by Applicant cannot be predictably made or used by the ordinary artisan.
Not knowing, absent further experimentation and screening, which modifications function and which do not, when, as set forth above, even a single change of an antigen can unpredictably affect structure and function of the antibody, leads to one having no predictability or expectation of success for the function of any given chimeric antigen receptor. Such random experimentation to identify at a later time what structure or variant or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Since the prior art at the effective filing date of the present application did not provide guidance for a method to treat B-cell neoplasms expressing a mutant isoform of CD19, it is incumbent upon the instant specification to do so. The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make and use the claimed invention.
CONCLUSION
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is require to make and use the invention beyond the scope of using a SFK inhibitor and/or CD20/CD22 CART cell to inhibit a B-cell neoplasm that expresses a CD19 isoform comprising a deletion in exons 2, 5, and/or 6.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 1-21 of U.S. Patent No 12,606,636 (Brogdon et al., Patented 4/21/2026).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B-ALL comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-18 of U.S. Patent No 12,594,321 (Brannetti et al., Patented 4/07/2026).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B-ALL comprising administering CART20 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-27 of U.S. Patent No 12,344,657 (Bitter et al., Patented 6/01/2025).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-23 of U.S. Patent No 11,975,026 (Engles et al., Patented 5/07/2024).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-38 of U.S. Patent No 11,872,249 (Brannetti et al., Patented 1/06/2024).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B-ALL comprising administering CART20 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 28-32 of U.S. Patent No 11,149,076 (Bitter et al., Patented 10/19/2021).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B-ALL comprising administering CART22 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-20 of U.S. Patent No 11,273,219 (June et al., Patented 3/15/2022).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-25 of U.S. Patent No 10,774,388 (Bedoya et al., Patented 9/15/2020).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-28 of U.S. Patent No 10,603,378 (June et al., Patented 3/31/2020).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 7-9 are rejected on the grounds of nonstatutory double patenting over claims 1-35 of U.S. Patent No 10,253,086 (Bitter et al., Patented 4/09/2019).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 5-7of U.S. Patent No 9,499,629 (June et al., Patented 11/22/2016).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 15-30 of U.S. Patent No 9,481,728 (June et al., Patented 11/01/2016).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 1-16 and 18-29 of U.S. Patent No 9,101,584 (June et al., Patented 8/11/2015).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 1-28 of U.S. Patent No 8,916,381 (June et al., Patented 12/23/2015).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2 and 8-9 are rejected on the grounds of nonstatutory double patenting over claims 26- 29 of U.S. Patent No 8,906,682 (June et al., Patented 12/09/2014).
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for treating leukemia comprising administering CART19 cells of cited patent anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2, 7-9 are provisionally rejected on the grounds of nonstatutory double patenting over claims 2-4, 6, 8-11, 14, 16, 35-39 of copending Application No. 18/884,583. This is a provisional double patenting rejection since the conflicting claims have not yet been patented.
The subject matter claimed in the instant application is disclosed in the cited application as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited application anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2, 7-9 are provisionally rejected on the grounds of nonstatutory double patenting over claims 39-56 of copending Application No. 18/036,749. This is a provisional double patenting rejection since the conflicting claims have not yet been patented.
The subject matter claimed in the instant application is disclosed in the cited application as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited application anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Claims 1-2, 7-9 are provisionally rejected on the grounds of nonstatutory double patenting over claims 1, 5-6, 9-10, 20, 22-28, 31, 33-34, 36, 40, 50-53, 55-61 of copending Application No. 16/435,257. This is a provisional double patenting rejection since the conflicting claims have not yet been patented.
The subject matter claimed in the instant application is disclosed in the cited application as follows: the method for treating B cell neoplasm comprising administering CART19 cells of cited application anticipates the method of instant application. It is clear that elements of the cited patent claims are to be found in instant claims.
Since the instant application claims are anticipated by cited patent claims, said claims are not patentably distinct.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631
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