DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Applicant’s submission filed 12 December 2024 has been entered. Claims 98 and 145 have been amended, with support for the amendments found on Page 2 of the instant Specification. Therefore, claims 98, 128-146, and 148-154 remain pending for examination on the merits as reading on the elected invention. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 98, 128-146, 148, and 152-154 under 35 USC 103 over Brahmandam et al in view of Gattinoni et al and Pistoia et al
The amendment to independent claim 98 requiring the composition to not comprise T cells expressing a recombinant TCR or T cells expressing a chimeric antigen receptor (CAR) obviates the current rejection on record. Therefore, the rejection is withdrawn.
However, Applicant’s arguments have been addressed in regards to the claims as amended:
For completeness of record, and because some of the new rejections rely on previously cited art, the Examiner has considered Applicant’s arguments with regard to Gattinoni et al, but is not convinced of error.
Applicant has traversed the rejection, asserting in Page 7 of the Remarks filed 12 December 2012 that Gattinoni et al do not teach or suggest a composition comprising the CTL and memory phenotype as claimed, wherein the T cells do not express a CAR or recombinant TCR. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Further, it is noted that the composition encompassed by independent claim 98 is rendered obvious over newly cited Maeurer. However, the disclosure of Gattinoni et al remains relevant over claim 139, for similar reasons as stated previously. Gattinoni et al is (and was) a secondary reference relied upon to establish a mixed lymphocyte population comprising CD8+ effector and central memory cells and T memory stem cells could comprise up to 80% central and effector memory cells and 15% T memory stem cells. The claimed composition becomes obvious when considered in combination with the other cited art.
RE: Rejection of claims 98, 128-146, and 149-154 under 35 USC 103 over Brahmandam et al in view of Gattinoni et al, Pistoia et al, and Ohno et al as evidenced by Krumm et al
The amendment to independent claim 98 requiring the composition to not comprise T cells expressing a recombinant TCR or T cells expressing a chimeric antigen receptor (CAR) obviates the current rejection on record. Therefore, the rejection is withdrawn.
However, Applicant’s arguments have been addressed in regards to the claims as amended:
For completeness of record, and because some of the new rejections rely on previously cited art, the Examiner has considered Applicant’s arguments with regard to Ohno et al, but is not convinced of error.
Applicant has traversed the rejection, asserting in Page 7 of the Remarks filed 12 December 2012 that Ohno et al do not teach or suggest a composition comprising the CTL and memory phenotype as claimed, wherein the T cells do not express a CAR or recombinant TCR. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Further, it is noted that the composition encompassed by independent claim 98 is rendered obvious over newly cited Maeurer. However, the disclosure of Ohno et al remains relevant over claim 149, for similar reasons as stated previously. Ohno et al is (and was) a secondary reference to establish culturing a mixed lymphocyte population culturing in the presence of IL-2, IL-4, IL-6, INF-γ, and IL-1β. The claimed composition becomes obvious when considered in combination with the other cited art.
New Grounds of Rejection
Claim Interpretation
Instant claims 132-133 recite limitations separated by the conjunction “and/or”. Unless
otherwise specified, the Examiner is interpreting these limitations as alternatives, wherein only one limitation that is separated by an “and/or” conjunction is required.
Furthermore, claims 149-151 further define the method by which the isolated cell composition of claim 98 is obtained. These are product-by-process limitations. Product-by-process limitations are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the CD8+ T cells enriched from source cells imparts any particular structure or significance to the CD8+ T cells. Thus, the claim will be interpreted as if the expansion of the CD8+ T cells in the presence of IL-2, IL-4, IL-6, INF-γ, and IL-1β fulfills the enrichment step that is required by instant claim 149 and its dependents thereof.
Claim Rejections - 35 USC § 103
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 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.
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 98, 128-146, 148, and 152-154 are rejected under 35 U.S.C. 103 as being unpatentable over Maeurer (US 2017/0107490 A1, of record on IDS filed 12 December 2019) as evidenced by Pistoia et al (Front Immunol, 2018, of record) in view of Gattinoni et al (Nat Med, 2011, of record).
Maeurer et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Gattinoni et al and Pistoia et al are considered prior art under 35 USC 102(a)(1).
Regarding claims 98, 129, 131, 134-141, 143-144, and 148: Maeurer discloses a method of preparing a population of clinically relevant, antigen edited lymphocytes using a composition of predefined cytokines (Paragraphs [0001], [0019]). Maeurer further discloses that the prepared population is formulated into a composition with a pharmaceutically acceptable carrier and administered to subject in need thereof, including a subject suffering from cancer or an infectious disease (Paragraphs [0027]-[0028], [0193]-[0197], [0200]). With that, Maeurer further discloses that at least 4x106 of the clinically relevant lymphocytes are administered to the subject (Paragraph [0202]).
As such, Maeurer discloses that the clinically relevant lymphocytes are mixed populations comprising, at least, CD8+ effector cells, central memory T cells (TCM-cells), peripheral – or effector – memory T cells (TPM-cells/TEM-cells), stem cell memory T cells (TSCM), T cell precursors (naïve T cells), and gamma-delta T cells (Paragraphs [0075], [0164]-[0166], [0179]-[0191]). Maeurer further discloses the clinically relevant lymphocytes are mixed populations comprising, at least 2% effector memory T cells (TEM-cells), at least 1% T cell precursors, and at least 1% gamma-delta T cells (Paragraphs [0179], [0187]-[0188], [0191]). Maeurer further discloses the clinically relevant lymphocytes are produced by culturing autologous or allogenic lymphocytes in vitro with cytokine cocktails and one or more expansion antigens in order produce the clinically relevant, antigen edited lymphocytes (Paragraphs [0065]-[0068], [0073]-[0075], [0088]-[0092], [0102]-[0144]). Maeurer exemplifies expanded populations of lymphocytes, following culturing in cytokines and antigenic stimulation, wherein at least 50%, 60%, and 70% are CD8+ central memory T cells (TCM-cells, CD8+, CCR7+, CD45RA-), at least 30%, 40%, and 40% effector memory T cells (TEM-cells and TEMRA-cells, CD8+, CCR7-, CD45RA-), and at least 1% CD8+ memory precursors (CD8+, CCR7+, CD45RA+) (Examples 31-32; Figures 22a, 23). The methods and compositions of Maeurer do not include recombinant T cell receptors (TCRs) or chimeric antigen receptors (CARs).
Maeurer further discloses that the clinically relevant, antigen edited lymphocytes are polyclonal and respond to multiple antigens, including twelve different target antigens (Paragraphs [0124]-[0125], [0129]-[0131], [0170]-[0171], [0278]-[0279]).
Maeurer does not specifically disclose the exact percentages of T memory stem cells, as is required by at least instant claim 98.
Gattinoni et al, however, disclose enriched CD8+ T cells, wherein the percentages of central and effector memory T cell, T memory stem cell, and naïve T cell subsets are analyzed within samples following antigenic stimulation (Title; Page 7, Discussion; Page 9, Generation of mesothelin-specific T cells; Figure 2E). More specifically, Gattinoni et al disclose an enriched population of CD8+ T cells comprising about 80% central and effector memory cells, about 20% T memory stem cells, and about 2% naïve cells (Figure 2E).
Therefore, it would have been prima facie obvious to modify the method of Maeurer such that the percentage of central and effector memory T cells and T memory stem cells is at least 95% of the composition while the percentage of naïve T cells comprised within the composition is less than 5%. One of ordinary skill before the effective filing date of the invention would have been motivated to have a composition comprising an enriched population of CD8+ memory cells, as they allow for the fast delivery of immune effector functions upon administration into a subject while also providing for long-term immunological memory, and would have had a reasonable expectation of success based on the disclosure of Maeurer (Paragraphs [0012]). See MPEP § 2143(I)(G). With that, it also would not have been outside the skillset of the ordinary artisan to tune the composition for particular percentages of CD8+ central and effector memory T cells, T memory stem cells, and naïve T cells. More specifically, it would not have been outside the skillset of the ordinary artisan to provide a composition of CD8+ T cells comprising about 80% central and effector memory cells, about 15% memory stem cells, and about 5% naïve cells – as is necessarily suggested by Figure 2E of Gattinoni et al. See MPEP § 2144.05(II).
Consequently, Maeurer as modified by Gattinoni et al render obvious a method of treating cancer or an infectious disease, wherein a subject is administered a population of clinically relevant, antigen edited lymphocytes comprised in a pharmaceutically acceptable carrier, wherein the clinically relevant, antigen edited lymphocytes are gamma-delta T cells – which inherently consist of a proportion of Vδ2 T cells and Vδ1 T cells (claim 148; See Pistoia et al, Page 2) – and at least 4x106 CD8+ T cells capable of binding to twelve target antigens (claims 129, 131), which are comprised of about 80% central and effector memory T cells (claims 138-141), about 15% T memory stem cells (claims 134-136), and less than 5% naïve T cells (claims 143-144). See MPEP § 2144.05(I). As this composition of clinically relevant, antigen edited lymphocytes comprised in a pharmaceutically acceptable carrier comprises CD8+ T cells having greater than 95% of a memory phenotype (claim 137) – which the Examiner arrived to by combining the above subset percentages of at least 80% central and effector memory T cells and at least 15% T memory stem cells – and is silent to the inclusion of recombinant T cell receptors or chimeric antigen receptors, this modified method therefore reads on the method of instant claim 98.
Regarding claims 128 and 152: Following the discussion of claim 98, Maeurer further discloses that the target peptide antigens are tumor associated antigens (claim 128), including Survivin (claim 152)(Paragraphs [0072], [0109], [0144]; Example 7). This therefore reads on the method of the instant claims.
Regarding claim 130: Following the discussion of claim 98, Maeurer further discloses that the composition of clinically relevant lymphocytes is at least 90% T cells (Paragraph [0033]; Figure 4b). This therefore reads on the method of the instant claim.
Regarding claim 132-133 and 153-154: Following the discussion of claims 98 and 128, Maeurer further discloses that, in addition to the tumor associated antigens, the clinically relevant lymphocytes can also be specific for a pathogen associated antigen – or antigens related to bacteria, viruses and other microorganism (claim 132) – including EBV (claims 133, 153-154)(Paragraphs [0068], [0070], [0147]-[0148]). This therefore reads on the method of the instant claims.
Regarding claim 142: Following the discussion of claim 98, Maeurer further discloses that the percentage of terminally differentiated T cells is at least 1% (Paragraphs [0013], [0189]-[0190]). Therefore, since “at least 1%” also includes 1%, less than 10% of the CD8+ T cells will be terminally differentiated. This therefore reads on the method of the instant claim.
Regarding claim 145: Following the discussion of claim 98, Maeurer further discloses that about 40% of the CD8+ T cells are polyfunctional when activated in vitro (Paragraphs [0132], [0153]-[0156], [0170], [0278]-[0279]; Example 25; Figure 16). This therefore renders obvious the method of the instant claim. See MPEP § 2144.05(I).
Regarding claim 146: Following the discussion of claim 98, Maeurer further discloses an experimental embodiment wherein the clinically relevant, antigen edited lymphocytes are 94% CD8+ T cells and only about 4% CD4+ T cells (Figure 16). This therefore reads on the method of the instant claim.
Claims 98, 128-146, 148-149, and 152-154 are rejected under 35 U.S.C. 103 as being unpatentable over Maeurer (US 2017/0107490 A1, of record on IDS filed 12 December 2019) as evidenced by Pistoia et al (Front Immunol, 2018, of record) in view of Gattinoni et al (Nat Med, 2011, of record), and further in view of Ohno et al (US 5874307 A, of record) as evidenced by Krumm et al (The Protein Society, 2014, of record).
The discussion of Maeurer as modified by Gattinoni et al as evidenced by Pistoia regarding claim 98 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Maeurer as modified by Gattinoni et al as evidenced by Pistoia et al render obvious claims 98, 128-146, 148, and 152-154. Ohno et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2) and Krumm is considered prior art under 35 USC 102(a)(1).
Regarding claim 149: The instant claim includes product-by-process language. The effect of the product-by-process language is discussed above – see Claim Interpretation – and included herein.
Accordingly, following the discussion of claim 98, Maeurer further discloses that the clinically relevant lymphocytes – which include CD8+ T cells – can be cultured or incubated in the presence of one or more cytokines. As such, Maeurer discloses that the one or more cytokines include IL-2, IL-4, and IL-1β (Paragraph [0090]).
The combination of Maeurer as evidenced by Pistoia et al and Gattinoni et al do not disclose culturing the CD8+ T cells in the presence of IL-2, IL-4, IL-6, INF-γ, and IL-1β – as is required by instant claim 149.
Ohno et al, however, disclose culture methods of CD8+ cytotoxic T lymphocytes that allow for the downstream use for clinical treatments of tumors, or adoptive immunotherapies (Abstract).
As such, Ohno et al disclose the culture of the cytotoxic T lymphocytes in medium comprising IL-1, IL-2, IL-4, IL-6, and INF-γ (Column 5, Lines 10-15). It is of note that IL-1 inherently comprises IL-1β (Krumm et al, Page 527, IL-1).
Therefore, it would have been prima facie obvious to modify the combined method of Maeurer as evidenced by Pistoia et al and Gattinoni et al to include IL-1β, IL-2, IL-4, IL-6, and INF-γ within the culture medium, as indicated in Ohno et al as evidenced by Krumm et al. One of ordinary skill before the effective filing date of the invention would have been motivated to culture the CD8+ T cells in a culture medium known to enhance tumor killing capabilities, and would have had a reasonable expectation of success based on the disclosure of Ohno et al (Columns 4-6, Example 1). See MPEP § 2143(I)(G).
Consequently, Maeurer as evidenced by Pistoia et al as modified by Gattinoni et al and further in view of Ohno et al as evidenced by Krumm et al render obvious a method of treating cancer or an infectious disease, wherein the clinically relevant CD8+ T cells are cultured in the presence of IL-1β, IL-2, IL-4, IL-6, and INF-γ. This therefore renders obvious the method of the instant claim.
Claims 98, 128-146, and 148-154 are rejected under 35 U.S.C. 103 as being unpatentable over Maeurer (US 2017/0107490 A1, of record on IDS filed 12 December 2019) as evidenced by Pistoia et al (Front Immunol, 2018, of record) in view of Gattinoni et al (Nat Med, 2011, of record) and Ohno et al (US 5874307 A, of record) as evidenced by Krumm et al (The Protein Society, 2014, of record), and further in view of Almaasbak et al (US 2019/0062706 A1, of record on IDS filed 12 December 2019).
The discussion of Maeurer as modified by Gattinoni et al as evidenced by Pistoia et al regarding claim 98, and the discussion of Maeurer as evidenced by Pistoia et al in view of Gattinoni et al and Ohno et al as evidenced by Krumm et al regarding claim 149 can be observed above and are each relied upon herein, the content of which is incorporated in its entirety. Maeurer as evidenced by Pistoia et al and modified by Gattinoni et al render obvious claims 98, 128-146, 148, and 152-154. Maeurer as evidenced by Pistoia et al and taken in view of Gattinoni et al and Ohno et al as evidenced by Krumm et al render obvious claims 98, 128-146, 148-149, and 152-154. Almaasbak et al is considered prior art under 35 USC 102(a)(2).
Regarding claims 150-151: The instant claim includes product-by-process language. The effect of the product-by-process language is discussed above – see Claim Interpretation – and included herein.
Accordingly, following the discussion of claim 149, Maeurer further discloses that the clinically relevant, antigen edited lymphocytes are stimulated with peptides or peptide fragments of the clinically relevant antigens, and then allowed to expand in culture for seven days (Paragraphs [0029], [0066]-[0069], [0121]-[0125], [0132]). Maeurer further discloses that the clinically relevant antigen can also include an MHC class I molecule (Paragraph [0125]).
None of Maeurer as evidenced by Pistoia et al as modified by Gattinoni et al, or Maeurer as evidenced by Pistoia et al as modified by Gattinoni et al and Ohno et al as evidenced by Krumm et al teach that the clinically relevant antigens are attached to paramagnetic aAPCs having an MHC class I ligand and a co-stimulatory ligand, nor that the cells and aAPCs are incubated in the presence of a magnetic field for at least one minute – as is required in claims 150-151.
Almaasbak et al, however, disclose compositions of expanded T cell populations, methods for the expansion of T cell populations, and methods for using such populations of cells (Abstract).
As such, Almaasbak et al disclose contacting and enriching T cells with aAPCs, which include peptides presented by the major histocompatibility complex (MHC) class I proteins on the surface of the aAPCs (Paragraphs [0002], [0004], [0061], [0064]). Almaasbak et al further disclose that the aAPCs are paramagnetic beads which have a CD28 co-stimulatory ligand attached, and that the paramagnetic aAPCs and T cells are incubated in the presence of a magnetic field for 30 minutes (Paragraphs [0064], [0113], [0123]-[0124], [0139]-[0142], [0151]-[0157], [0162]-[0167], [0174]-[0177]).
Therefore, it would have been prima facie obvious to substitute the MHC/peptide antigen presentation complex of Maeurer for the paramagnetic aAPCs of Almaasbak et al, as doing so would be a simple substitution of one antigen presentation technique for another. See MPEP § 2143(I)(B). One of ordinary skill before the effective filing date of the invention would have recognized that the two techniques – and complex/aAPC therein – are functionally comparable, and thereby would have been able to substitute the techniques with predictable results.
Consequently, the method of Maeurer as evidenced by Pistoia et al as modified by Gattinoni et al, Ohno et al as evidenced by Krumm et al, and Almaasbak et al renders obvious a cancer or infectious disease treatment method wherein the clinically relevant, antigen edited T lymphocytes are enriched with a paramagnetic aAPC comprising MHC class I and CD28 co-stimulatory ligands (claim 150) for 30 minutes in the presence of a magnetic field, and then expanded in culture for seven days (claim 151). This therefore renders obvious the method of the instant claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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