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
The amendment filed June 12, 2025, is acknowledged and has been entered. Claim 40 has been amended.
The species under consideration are:”
A. CD19: the first antigen-binding CAR molecule.
B. GUCY2C or CEA: the second antigen-binding molecule.
C. 4-1 BB: the intracellular domain.
Claim Status
Claims 25-57 are pending and under examination.
Grounds of Rejection Withdrawn
Unless specifically reiterated below, Applicant’s amendments have obviated or rendered moot the grounds of objection and rejection set forth in the previous Office action mailed.
Grounds of Rejection Maintained
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 25, 26, 28-33, 35, 38-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2017/0209492 A1, IDS (June et al).
In regards to instant claims 25, 26, 28-33 and 40, June et al discloses methods of preparing a composition comprising a first population of T cells comprising a first CAR binding a first antigen, and a second population of T cells comprising a second CAR binding a second antigen (¶ 0029, “a CD4+ T cell comprising a CAR (the CAR.sup.CD4+) comprising an antigen binding domain; a transmembrane domain; and an intracellular signaling domain; and a CD8+ T cell comprising a CAR (the CAR.sup.CD8+) comprising an antigen binding domain; a transmembrane domain; and an intracellular signaling domain; wherein the CAR.sup.CD4+ and the CAR.sup.CD8+ differ from one another" and wherein the intracellular signaling is 4-1BB or CD3 zeta (see ¶ 0288, ¶ 0317 and ¶ 0322); wherein the second antigen is a tumor antigen (¶ 0130; "… the CAR.sup.CD8+ comprises an antigen binding domain specific for a tumor antigen selected from ... tumor antigens well known in the art…" see also ¶ 0375) and is different from the first antigen (¶ 0129; "In an embodiment, the CAR.sup.CD4+ comprises an antigen binding domain specific for ... CD19").
In the interest of compact prosecution, the examiner is interpreting instant claim 40 as if it depends from claim 25. Regarding instant claim 40, the invention disclosed by June et al provides vectors in which a DNA of the taught invention is inserted and specifically identify lentiviruses as suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells (specification, p. 44, ¶0534). UPenn also sites additional advantages of using lentiviral vectors, such, as their low immunogenicity and ability to transduce non-proliferating cells (specification, p. 44, ¶0534).
Regarding instant claims 32-33, June et al further discloses that the first antigen comprises a cell surface molecule of a B cell, specifically CD19 (see ¶ 0405). Regarding instant claim 38, the second binding domain comprise a modified TCR ( ¶0319). Regarding instant claim 39, it is first noted that the T cells comprise a polynucleotide encoding IL-12, but the mixed population of cells can also comprise cells genetically modified to express IL-12 (¶ 0718).
In regards to instant claim 35, June et al discloses that tumor antigens are produced by tumor cells, eliciting T-cell mediated immune responses, and that selection of the antigen binding domain of the invention will depend on the particular type of cancer to be treated. Specifically, at ¶0375, June et al discloses that tumor antigens are well known in the art and include, for example, carcinoembryonic antigen (CEA).
Therefore, the prior art is deemed to anticipate the instant claims absent a showing otherwise.
Applicant has traversed the rejection and argued that:
“the claimed method does not require separately contacting cells with different vectors and subsequently combining the modified cells after they are independently transduced. June does not teach or suggest a method of obtaining a mixed cell population comprising "contacting cells with (i) a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen and (ii) a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen to obtain a mixed population of modified cells," as recited in claim 25. June only teaches contacting different cells with different vectors and then actively mixing the modified cells. Thus, the method steps, the cell products, and the underlying technical strategy of June are different from the method recited in claim 25.”
Applicant has further submitted:
“MPEP 2111 requires that the claims be interpreted to be consistent with the specification. Applicant respectfully submits that it seems that the Office's interpretation of the term "a mixed population of modified cells" is not consistent with Applicant's description of "a mixed population of modified cells" as set forth, for example, in paragraphs [0011] to [0014], [00194], and the Examples of the specification. The specification describes "a mixed population of modified cells" as being produced from "contacting cells with (i) a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen and (ii) a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen to obtain a mixed population of modified cells," as recited in claim 25. It seems that the Office's interpretation of the term "a mixed population of modified cells" is the combination of mixing two different populations of cells after being separately transduced with different vectors, as disclosed in June, which is inconsistent with the description provided in the specification and as recited in claim 25.”
In response, these arguments are not found persuasive because neither the claims nor the specification limit the claimed methods to contacting a single population of cells with both a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen and a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen. The claims merely recite contacting cells with a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen and a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen and do not require the same cells to be contacted with both vectors and the specification supports this reasonably interpretation.
Notably, in ¶ 172 states the invention encompasses “introducing a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen into a first population of cells to obtain a first population of modified cells; introducing a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen into a second population of cells to obtain a second population of modified cells; and administering an effective amount of the first and second population of modified cells to the subject” and ¶ states “for a mixed population of three different modified cells including (1) modified cells containing an antigen binding domain for expanding and/or maintaining the modified cells, (2) modified cells containing an antigen binding domain for killing a target cell, and (3) modified cells containing both the antigen binding domains of expanding and/or maintaining the modified cells and of killing a target cell (in a single modified cell), a therapeutically effective amount of (1), (2), and (3) can be administered sequentially in any order (1, 2, 3; 2, 3, 1; 3, 1, 2; 1, 3, 2; 2, 1, 3; or 3, 2, 1) or simultaneously (1+2+3 at the same time). Moreover, two of the three modified cells can be combined and administered together with the third one being administered before or after the combination. Accordingly, the specification supports that the claims encompass contacting cells with a first vector and contacting separate cells with a second vector and then combining the cells to obtain a mixed population and the claims do not expressly require that a single population of cells is contacted with a first and second vector.
It appears that Applicant would like the claims to be limited to contacting a single population of cells with a first vector and a second vector, but did not amend the claims accordingly, so it is suggested that the claims be amended to limit the claims to Applicant’s desired scope.
Claims 25-33, 38-48 and 53-57 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2015/0329640 A1 (Finer).
In regards to instant claims 25-28, 32-33, 41-43 and 47-48 and 56-57, Finer discloses methods of preparing a composition comprising a mixed population of immune effector T cell comprising one or more different vectors encoding different chimeric antigen receptors (CAR) with a proportion expressing more than one different CAR protein (i.e., due to transfection efficacy some cells with express both CARs, some the CAR on the first vector and some the CAR on the second vector and wherein the CARs can bind a B cell antigen and a tumor antigen such as CD19 and CD37 (see ¶ 0045, ¶0049, ¶0094, ¶0102 and ¶ 0134-0144). In regards to instant claims 29-31 and 44-46, the CAR comprises a transmembrane domain and an intracellular signaling domain such as 4-1BB (CD137) or CD3 zeta (see ¶ 0048).
In regards to instant claims 38 and 53, the chimeric antigen receptor can comprise a scTCR (see ¶ 0050). Regarding instant claims 39 and 54, it is noted that the T cells comprise a polynucleotide encoding IL-12. Regarding instant claims 40 and 55, the vectors can be lentiviral vectors (see ¶ 010).
Therefore, the prior art is deemed to anticipate the instant claims absent a showing otherwise.
Applicant has traversed the rejection and argued that:
“Applicant respectfully submits that Finer is directed to CAR molecules targeting the CD37 antigen for treating B-cell malignancies. Finer, abstract and paragraphs [0004] and [0008]. As is well-known, B-cell malignancies are associated with blood cancer. Finer is not concerned with CAR molecules binding to a solid tumor. Therefore, in paragraph [0143], when Finer describes that a "mixture of different expression vectors can be used in genetically modifying a donor population of immune effector cells, wherein each vector encodes a different chimeric antigen receptor protein," Finer is not describing two expression vectors encoding two different CAR molecules "wherein the first antigen binding molecule binds a cell surface molecule of a B cell and the second antigen binding molecule binds a solid tumor antigen," as recited in claim 25.”
Applicant has further submitted:
“Finer only mentions that "a mixture of different expression vectors can be used." Finer does not teach or suggest a method to obtain a mixed population of modified cells comprising the steps of "contacting cells with (i) a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen and (ii) a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen to obtain a mixed population of modified cells," as recited in claim 25. As discussed above, claim 25 is directed to a method of obtaining a mixed population of modified cells requiring the performance of specific steps. For a reference to anticipate claim 25, the reference must teach each of the recited steps.”
In response, these arguments are not found persuasive because the specification states at ¶ 131 that “Different types of solid tumors are named for the type of cells that form them (such as sarcomas, carcinomas, and lymphomas)” and lymphomas are known to include B cell lymphomas that express CD37, such that a CAR targeting CD37 meets the limitation of an antigen binding molecule that binds a solid tumor antigen. In further response, this position is supported by Stevenson et al (Cancer Biology, 9:39-147, 1999) that discloses that lymphoma cells can be obtained from a biopsy of a solid tumor and that CD37 is expressed in B cell lymphomas (see page 139 and Table 1). Then with respect to Finer disclosing that a mixture of different expression vectors can be used and that the expression vectors can encode CARs that can bind CD19 and CD37, the prior art meets the limitation of the claims, e.g., with respect to claim 25, “contacting cells with (i) a first vector comprising a polynucleotide encoding a first antigen binding molecule that binds a first antigen and (ii) a second vector comprising a polynucleotide encoding a second antigen binding molecule that binds a second antigen to obtain a mixed population of modified cells”.
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.
Claim 25, 26, 28-35, 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0209492 A1, IDS (June et al) and US 2018/0153977 A1 (Wu et al).
The teachings of June et al are above.
Wu et al discloses a humanized scFv CD19 fragment comprising the amino acid sequence of SEQ ID NO: 43 which is 100% identical to instant SEQ ID NO: 5 (see alignment).
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It would be obvious to a person having ordinary skill in the art to replace the CD19 antigen binding molecule taught by June’s methods with the humanized scFv CD19 comprising amino acid sequence of SEQ ID NO: 43 because this specific construct has been used to target CD19-expressing B cell malignancies.
Accordingly, using the scFv of the prior art of Wu in the methods and constructs of June would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant has traversed the rejection and has essentially argued that June et al is not applicable for an obviousness rejection for the reasons set forth above which the examiner did not find persuasive there or here for the same reasons and because “the Office provides no reason to combine the teachings of June and Wu. Even if the teachings of June and Wu were combined, there would be no reasonable expectation of success in arriving at the method recited in claim 25. The teachings of June are focused on tailoring CAR constructs to match the CD4* and CD8* T cell biology for hematologic targets. Wu is concerned with CD19-specific CARs for B-cell malignancies, which are blood cancers. There is no teaching or suggestion in June or Wu to combine each of their expression vectors with an unrelated expression vector encoding CAR binding a solid tumor antigen for introducing them into the same population of cells to obtain a mixed population of cells”.
In response, June discloses preparing compositions of cells expressing a CAR that binds CD19 and CEA, while Wu provides a known humanized scFv CD19 fragment that can be used in a CAR vector to target CD19 such that using the scFv of the prior art of Wu in the methods and constructs of June would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Finally, Applicant’s arguments submits that the claimed inventions provides surprising results but the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the results being unexpected are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted.
Claim 25-34, 38-49 and 53-57 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0329640 A1 (Finer) and US 2018/0153977 A1 (Wu et al)
The teachings of Finer are above.
Wu et al discloses a humanized scFv CD19 fragment comprising the amino acid sequence of SEQ ID NO: 43 which is 100% identical to instant SEQ ID NO: 5 (see alignment).
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It would be obvious to a person having ordinary skill in the art to replace the CD19 antigen binding molecule taught by Finer’s methods and compositions with the humanized scFv CD19 comprising amino acid sequence of SEQ ID NO: 43 because this specific construct has been used to target CD19-expressing B cell malignancies.
Accordingly, using the scFv of the prior art in the constructs of Finer would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant has traversed the rejection and has essentially argued that Finer et al is not applicable for an obviousness rejection for the reasons set forth above which the examiner did not find persuasive there or here for the same reasons and because “the Office provides no reason to combine the teachings of Finer and Wu. Finer and Wu, both are concerned with treating B-cell malignancies using B-cell antigens, such as CD37 and CD19. Even if these two references were combined, it would at most suggest a dual B-cell antigen targeting approach, for example, to mitigate antigen escape within B-cell malignancies. Hence, there is no reasonable expectation of success in arriving at the claimed method and composition, even if the teachings were combined”.
In response, as set forth above CD37 meets the limitation of a solid tumor antigen Wu provides a known humanized scFv CD19 fragment that can be used in a CAR vector to target CD19 such that using the scFv of the prior art of Wu in the methods and constructs of Finer would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Finally, Applicant’s arguments submits that the claimed inventions provides surprising results but the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the results being unexpected are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted.
Claim 25, 26, 28-33, 35-36, 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0209492 A1, IDS (June et al), US 2017/0355776 A1 (Xiao et al) and Finney et al (Journal of Clinical Investigation (129(5):2123-2132).
The teachings of June et al are above.
Xiao et al discloses a CAR T construct that binds GUCY2C (also called guanylyl cyclase C, GCC) and discloses the amino acid of the binding domain comprises the amino acid sequence of SEQ ID NO:14 which is 100% identical to instant SEQ ID NO: 11 disclosed in claim 36 (see alignment).
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RESULT 1
US-15-685-670-14
(NOTE: this sequence has 56 duplicates in the database searched.
See complete list at the end of this report)
Sequence 14, US/15685670
Publication No. US20170355776A1
GENERAL INFORMATION
APPLICANT: Innovative Cellular Therapeutics CO., LTD.
TITLE OF INVENTION: Use of chimeric antigen receptor modified cells to treat cancer
FILE REFERENCE: SDS1.0028US1
CURRENT APPLICATION NUMBER: US/15/685,670
CURRENT FILING DATE: 2017-08-24
PRIOR APPLICATION NUMBER: PCT/CN2017/078740
PRIOR FILING DATE: 2017-03-30
PRIOR APPLICATION NUMBER: US62/317261
PRIOR FILING DATE: 2016-04-01
NUMBER OF SEQ ID NOS: 45
SEQ ID NO 14
LENGTH: 241
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic
Query Match 100.0%; Score 1283; Length 241;
Best Local Similarity 100.0%;
Matches 241; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
Qy 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
Qy 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
Qy 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
Qy 241 S 241
|
Db 241 S 241
Finney et al disclose that total level of CD19 in the marrow correlates with peak engraftment and persistence of CAR T cells in a patient (see page 2127, left column).
It would be obvious to a person having ordinary skill in the art to use the GUCY2C-specific CAR comprising an antigen-binding domain disclosed by Xiao to replace a CEA specific CAR of June along with CD19 CAR T cells because a GUCY2C-specific CAR can be used to treat colorectal cancer (see Figure 1 of Xiao), which is also a cancer mentioned in June (see ¶ 0314), while a CD19 CAR would help engraftment and persistence of CAR T cells in a patient.
Accordingly, using the GUCY2C-specific CAR comprising an antigen-binding domain disclosed by Xiao of the prior art in the methods and constructs of June would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant has traversed the rejection and has argued that “the Office provides no reason to combine the teachings of June, Xiao, and Finney. The therapeutic targets and strategies of the three cited references are fundamentally different. June and Finney are directed to hematologic B-cell malignancies. The Office only shows that Xiao discloses CAR targeting GUCY2C. There is no teaching or suggestion in these cited references of a single-step method of introducing two different expression vectors to obtain a mixed population of cells comprising CAR molecules targeting a B cell antigen and a solid tumor antigen. This combination of CAR molecules is a therapeutically different kind of treatment as it involves two different classes of antigens and requires different safety considerations. As discussed above, unless there is specific teaching or guidance to do so from the cited references, a person of ordinary skill in the art would not have any reason to introduce the expression vectors of a B-cell CAR and a solid tumor CAR in a single step to generate a mixed population of cells as it was not known before the earliest priority date of this application whether the mixed population of cells can be used to treat a disease without severe CRS. Hence there is no reasonable expectation of success in arriving at the claimed method and composition, even if the teachings were combined. As discussed above, combining CAR molecules for treating different categories of cancer would present significant and unaddressed challenges regarding optimal CAR design for disparate targets, vector compatibility, the potential for off-target toxicities, and complex manufacturing and dosing considerations, none of which are addressed by the cited references”.
In response, this argument is not found persuasive because the GUCY2C-specific CAR can be used to treat colorectal cancer (see Figure 1 of Xiao), which is also a cancer mentioned in June (see ¶ 0314), while a CD19 CAR would help engraftment and persistence of CAR T cells in a patient as set forth in the previous action.
Finally, Applicant’s arguments submits that the claimed inventions provides surprising results but the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the results being unexpected are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted.
Claim 25-33, 35-36, 38-48, 50-51 and 53-57 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0329640 A1 (Finer) US 2017/0355776 A1 (Xiao et al) and Finney et al (Journal of Clinical Investigation (129(5):2123-2132).
The teachings of Finer are above.
Xiao et al discloses a CAR T construct that binds GUCY2C (also called guanylyl cyclase C, GCC) and discloses the amino acid of the binding domain comprises the amino acid sequence of SEQ ID NO:14 which is 100% identical to instant SEQ ID NO: 11 disclosed in claim 36 (see alignment).
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12
867
media_image2.png
Greyscale
RESULT 1
US-15-685-670-14
(NOTE: this sequence has 56 duplicates in the database searched.
See complete list at the end of this report)
Sequence 14, US/15685670
Publication No. US20170355776A1
GENERAL INFORMATION
APPLICANT: Innovative Cellular Therapeutics CO., LTD.
TITLE OF INVENTION: Use of chimeric antigen receptor modified cells to treat cancer
FILE REFERENCE: SDS1.0028US1
CURRENT APPLICATION NUMBER: US/15/685,670
CURRENT FILING DATE: 2017-08-24
PRIOR APPLICATION NUMBER: PCT/CN2017/078740
PRIOR FILING DATE: 2017-03-30
PRIOR APPLICATION NUMBER: US62/317261
PRIOR FILING DATE: 2016-04-01
NUMBER OF SEQ ID NOS: 45
SEQ ID NO 14
LENGTH: 241
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic
Query Match 100.0%; Score 1283; Length 241;
Best Local Similarity 100.0%;
Matches 241; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
Qy 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
Qy 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
Qy 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
Qy 241 S 241
|
Db 241 S 241
Finney et al disclose that total level of CD19 in the marrow correlates with peak engraftment and persistence of CAR T cells in a patient (see page 2127, left column).
It would be obvious to a person having ordinary skill in the art to use the GUCY2C-specific CAR comprising an antigen-binding domain disclosed by Xiao to replace CD37 specific CAR of Finer along with CD19 CAR T cells because a GUCY2C-specific CAR can be used to treat colorectal cancer (see Figure 1 of Xiao), while a CD19 CAR would help engraftment and persistence of CAR T cells in a patient.
Accordingly, using the GUCY2C-specific CAR comprising an antigen-binding domain disclosed by Xiao of the prior art in the methods and constructs of Finer would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant has traversed the rejection and has argued that “the Office provides no reason to combine the teachings of Finer, Xiao, and Finney. The therapeutic targets and strategies of the three cited references are fundamentally different. Finer and Finney are directed to treating hematologic B-cell malignancies. The Office only shows that Xiao discloses CAR targeting GUCY2C. There is no teaching or suggestion in these cited references of a single-step method of introducing two different expression vectors into cells to obtain a mixed population of modified ceils comprising CAR molecules targeting a B cell antigen and a solid tumor antigen. This combination of CAR molecules is a therapeutically different kind of treatment as it involves two different classes of antigens and requires different safety considerations. As discussed above, unless there is specific teaching or guidance to do SO, a person of ordinary skill in the art would not have any reason to introduce the expression vectors of a B-cell CAR and a solid turnor CAR in a single step to generate a mixed population of cells as it was not known before the earliest priority date of the present application whether a mixed population of cells can be used to treat a disease without severe CRS. Hence there is no reasonable expectation of success in arriving at the claimed method and composition, even if the teachings were combined. As discussed above, combining CAR molecules for treating different categories of cancer would present significant and unaddressed challenges regarding optimal CAR design for disparate targets, vector compatibility, the potential for off-target toxicities, and complex manufacturing and dosing considerations, none of which are addressed by the cited references.”.
In response, this argument is not found persuasive because the GUCY2C-specific CAR can be used to treat colorectal cancer (see Figure 1 of Xiao), while a CD19 CAR would help engraftment and persistence of CAR T cells in a patient as set forth in the previous action.
Finally, Applicant’s arguments submits that the claimed inventions provides surprising results but the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the results being unexpected are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted.
Claim 25, 26, 28-33, 35 and 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0209492 A1, IDS (June et al) and Cherkassy et al. (J Clin Invest, 2016, 126 (8):3130-3144).
The teachings of June et al are above.
Cherkassy et al disclose a PD-1 dominant negative receptor (DNR) that, when co-transduced with a second-generation CAR, mediates enhanced T cell functional persistence as well as T cell resistance to tumor-mediated T cell inhibition (Fig. 9A-D).
It would be obvious to a person having ordinary skill in the art to combine the retroviral vector(s) encoding the PD-1 DNR taught by Cherkassy with CARs taught by June in order to directly counteract PD-1-mediated inhibition that can result in exhaustion and decreased effector functions. The ordinary artisan would be motivated to do as Cherkassy teaches that the strategic combination of costimulation and checkpoint blockade enhanced T cell function in the presence of tumor PD-L1 expression, resulting in long-term tumor-free survival following infusion of a single low dose of CAR T cells (Fig. 9E). One of ordinary skill would have a reasonable expectation of success as the PD-1 DNR taught by Cherkassy can be combined with CARs.
Accordingly, using the PD-1 DNR taught by Cherkassy of the prior art in the methods and constructs of June would be seen as combining prior art elements according to known methods to yield predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant has traversed the rejection and has argued that “Moreover, the Office provides no reason to combine the teachings of June and Cherkassky as they are directed to obtaining CAR for binding different classes of antigens and for treating different categories of cancer. The teachings of June are focused on tailoring CAR constructs to match the CD4* and CD&8* T cell biclogy for hematologic targets. Cherkassky is directed to enhancing the persistence and anti-tumor activity of mesathelin-targeted CAR T cells involving PD-1 DNR and CAR targeting mesothelin. There is no guidance or suggestion to obtain a mixed population of cells expressing CAR molecules targeting a B cell antigen and a solid tumor antigen. There is no teaching or suggestion in June or Cherkassky to combine each of their expression vectors with an unrelated expression vector encoding CAR binding a solid tumor antigen for introducing them into the same population of cells to obtain a mixed population of cells. As explained above, unless there is specific teaching or guidance to do so, a person of ordinary skill in the art would not have any reason to iniroduce the expression vectors of a B-cell CAR and a solid tumor CAR in a single step to generate a mixed population of cells as it was not known before the earliest priority date of this application whether the mixed population of cells can be used to treat a disease without severe CRS. Combining CAR molecules for treating different categories of cancer would present significant and unaddressed challenges regarding optimal CAR design for disparate targets, vector compatibility, the potential for off target toxicities, and complex manufacturing and dosing considerations, none of which are addressed by the cited references.”.
In response, this argument is not found persuasive because Cherkassy teaches that the strategic combination of costimulation and checkpoint blockade enhanced T cell function in the presence of tumor PD-L1 expression, resulting in long-term tumor-free survival following infusion of a single low dose of CAR T cells such that one would be motivated to combine the teachings of June and Cherkassay as set forth in the previous action.
Finally, Applicant’s arguments submits that the claimed inventions provides surprising results but the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See MPEP § 2145 generally for case law pertinent to the consideration of applicant's rebuttal arguments.
Accordingly, while the arguments of counsel about the results being unexpected are noted, they were not found persuasive as no affidavit or declaration including statements regarding the expectations of one of ordinary skill has been submitted.
Claim 25-33, 37-48 and 52-57 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0329640 A1 (Finer) and Cherkassy et al. (J Clin Invest, 2016, 126 (8):3130-3144).
The teachings of Finer are above.
Cherkassy et al disclose a PD-1 dominant negative receptor (DNR) that, when co-transduced with a second-generation CAR, mediates enhanced T cell functional persistence as well as T cell resistance to tumor-mediated T cell inhibition (Fig. 9A-D).
It would be obvious to a person having ordinary skill in the art to combine the retroviral vector(s) encoding the PD-1 DNR taught by Cherkassy with CARs taught by Finer in order to directly counteract PD-1-mediated inhibition that can result in exhaustion and decreased effector functions. The ordinary artisan would be motivated to do as Cherkassy teaches that the strategic combination of costimulation and checkpoint blockade enhanced T cell function in the presence of tumor PD-L1 expression, resulting in long-term tumor-free survival following infusion of a single low dose of CAR T cells (Fig. 9E). One of ordinary skill would have a reasonable expectation of success as the PD-1 DNR taught by Cherkassy can be combined with CARs.
Accordingly, using the PD-1 DNR taught by Cherkassy of the prior art in the methods and constructs of June would be seen as combining prior art elements according to known methods to yield predictable results. Furthermore, one of ordinary skill in the art would have expected success in practicing such methods as genetic engineering techniques were commonly used in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant has traversed the rejection and has argued that “the Office provides no reason to combine the teachings of June and Cherkassky as they are directed to obtaining CAR for binding different classes of antigens and for treating different categories of cancer. The teachings of June are focused on tailoring CAR constructs to match the CD4* and CD&8* T cell biclogy for hematologic targets. Cherkassky is directed to enhancing the persistence and anti-tumor activity of mesathelin-targeted CAR T cells involving PD-1 DNR and CAR targeting mesothelin. There is no guidance or suggestion to obtain a mixed population of cells expressing CAR molecules targeting a B cell antigen and a solid tumor antigen. There is no teaching or suggestion in June or Cherkassky to combine each of their expression vectors with an unrelated expression vector encoding CAR binding a solid tumor antigen for introducing them into the same population of cells to obtain a mixed population of cells. As explained above, unless there is specific teaching or guidance to do so, a person of ordinary skill in the art would not have any reason to iniroduce the expression vectors of a B-cell CAR and a solid tumor CAR in a single step to generate a mixed population of cells as it was not known before the earliest priority date of this application whether the mixed population of cells can be used to treat a disease without severe CRS. Combining CAR molecules for treating different categories of cancer would present significant and unaddressed challenges regarding optimal CAR design for disparate targets, vector compatibility, the potential for off target toxicities, and complex manufacturing and dosing considerations, none of which are addressed by the cited references.”.
In response, this argument is not found persuasive because Cherkassy teaches that the strategic combination of costimulation and checkpoint blockade enhanced T cell function in the presence of tumor PD-L1 expression, resulting in long-term tumor-free survival following infusion of a single low dose of CAR T cells such that one would be motivated to combine the teachings of Finer and Cherkassay as set forth in the previous action.
Finally, Applicant’s arguments submits that the claimed inventions provides surprising results but the arguments of counsel cannot take the place of evidence in the record. As set forth in MPEP 716.01:
Objective evidence which must be factually support