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 Claims
Claims 1-13 and 16-32 are pending.
Claims 1, 3-13, 16-20, 22-24 and 26-31 are amended.
Claim 32 is new.
Claims 1-13 and 16-32 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The U.S. effective filing date of all claims under examination is set at 08/24/2021 based on the EP21192853.6 application (filed on 08/24/2021).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
Drawings
The drawings are objected to because Figure 10 shows a graph on the right and second from the top appears to be misoriented.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. 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. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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 § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 6, 7, 11, 17-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites the phrase “the second recombinant construct encoding a…..”. There is insufficient antecedent basis for “the second recombinant construct” in the claim. Dependent claims 6, 7, 11, 17-21 are also included in this rejection.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title.
I would also add a 101 to this office action. Claim 1 is drawn to “an immune cell” expressing an IL-10...comprising “one or more recombinant constructs” that encodes IL-10. I think that doesn’t sound “markedly different” than naturally occurring immune cells expressing IL-10. So, I would reject at least claims 1, 3, 4, (maybe 12?), 13, 16, 24
Claims 1, 3, 4, 12, 13, 16 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to: “an immune cell” expressing an IL-10...comprising “one or more recombinant constructs” that encodes IL-10.
The claims are drawn to natural phenomenon because the claims recite natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: immune cells that express IL-10 and compositions comprising said immune cells in a “pharmaceutically acceptable carrier” - that can be water. MPEP 2106.04(d)(2) indicates a claim reciting a judicial exception is not directed to a judicial exception if it also recites additional elements(s) demonstrating the claim as a whole integrates the exception into a practical application. However, in the instant situation, there is no limitation that requires claimed products to be markedly different than products found in nature.
Im et al. (Journal of Biological Chemistry Volume 279, Issue 45, 5 November 2004, Pages 46818-46825) teaches that immunoregulatory cytokine interleukin 10 (IL-10) modulates the function of a diverse number of immune cells including T cells, macrophages and dendritic cells (Abstract and Pg 46818 column left first paragraph lines 1-4). They teach the location of the IL10 cytokine gene cluster in Figure 1. They also teach that Th1 and Th2 are two types of T helper cells that express IL-10 based on the type of stimuli received (Pg 46818 column right first full paragraph lines 1-2 and 5-11). They further teach the molecular mechanism of transcriptional regulation of IL10 gene at the chromatin level in Th1 and Th2 cells (Figures 3-5).
Therefore, the claimed invention is directed to a natural product/phenomenon without significantly more.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-10 and 12-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mohseni et al. (European Journal of Immunology 51, no. 10 (2021): 2522-2530; First Published Online 28 July 2021).
Mohseni et al. teaches chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 (Title). They teach generation of an expression cassette that contains IL-10 and the HLA-A2-CAR (Pg 2523 column right, first full paragraph, lines 1-2; Figure 1A: IL10-A2-CAR). They also teach the nucleic acid sequence of IL10-A2-CAR (Supplementary Table S4) which when translated to the amino acid sequence is a sequence that is comprised within and matches entirely from residue 19 to 178 of instant SEQ ID NO: 1(see Alignment 1 below). This means that the IL-10 taught by Mohseni et al. is a fragment of instant SEQ ID NO: 1.
Alignment 1: Alignment of instant SEQ ID NO: 1 (top) with the IL-10 sequence taught by Mohseni et al.
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Mohseni et al. also teaches in Figure 1A a cartoon of the lentiviral expression construct comprising recombinant IL-10 linked, via a T2A self-cleavage sequence, to a recombinant HLA-A2-CAR which comprises an extracellular scFv fragment targeting or recognizing HLA-A2, a CD28 hinge/transmembrane domain and a CD28 or CD3zeta intracellular signaling domain (Figure 1A, see below; and Pg 2523 column left, first full paragraph lines 3 to 6). They teach that Treg lines transduced with an expression cassette encoding for IL-10 secreted this cytokine at high levels (Figure 1D). They also teach that co-expression of IL-10 as an additional payload enhanced human Treg suppressive capacity (Fig. 3 and Supporting Information Fig. S9).
Figure 1: Figure 1A of Mohseni et al. showing the IL10-A2-CAR lentiviral expression construct
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Therefore, Mohseni et al. anticipates instant claims 1-10 and 12-13 and are rejected here.
Claim Rejections - 35 USC § 103 (First)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-10, 11, 12-13, 16-21 and 24-32 are rejected under 35 U.S.C. 103 as being unpatentable over Mohseni et al. European Journal of Immunology 51, no. 10 (2021): 2522-2530; First Published Online 28 July 2021) as applied to claims 1-10 and 12-13 above and further in view of June et al. (US20130288368A1 Date Published 2013-10-31), Guo et al. (Nat Immunol 22, 746–756, 2021; Published 24 May 2021) and Tschumi et al. (Journal for ImmunoTherapy of Cancer 2018;6:71, 1-9).
The teachings of Mohseni et al. are discussed above.
Mohseni et al. do not specifically teach immune cells comprising CARs that comprise an extracellular antigen recognition domain of an scFv derived from an antibody that recognizes CD19 or HER2; or pharmaceutical composition comprising therapeutically effective amount of an immune cell expressing an IL-10 fragment; or said pharmaceutical composition comprising additional therapeutic agent or therapy. Mohseni et al. also do not specifically teach a method of treating a cancer in a subject in need thereof comprising administering said pharmaceutical composition; or said method comprising administering genetically engineered T cells expressing a IL-10 fragment and a CAR, expanding said T cells and introducing said expanded T cells into the subject; or a method of enhancing antitumor activity in a subject in need thereof comprising administering said genetically engineered and expanded T cells that are introduced into the subject.
However, these deficiencies are made up in the teachings of June et al., Guo et al. and Tschumi et al.
June et al. teaches compositions and methods for treating cancer in a human comprising administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain (Abstract). They teach a CAR that targets CD19 wherein the antigen binding moiety portion is an anti-CD19 scFv comprising the amino acid sequence set forth in SEQ ID NO: 20 (paragraph [0136]). Alignment of the scFv recognizing CD19 of instant SEQ ID NO: 5 with SEQ ID NO: 20 taught by June et al. showed that they are an exact match at the same length of 242 amino acid residues (see Alignment 2 below).
Alignment 2: Alignment of instant SEQ ID NO: 5 (top) with the anti-CD19 scFv of SEQ ID NO: 20 as taught by June et al.
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June et al. also teaches ex vivo procedures of isolating cells from a human, genetically modifying said cells by transduction or transfection in vitro with a vector expressing a CAR, and administering CAR-modified cells to a human recipient to provide a therapeutic benefit wherein the CAR-modified cell can be autologous allogeneic, syngeneic or xenogeneic with respect to the recipient (paragraphs [0218] and [0278]).
June et al. further teaches a pharmaceutical composition comprising an anti-tumor effective amount of a population of the modified human T cells comprising a nucleic acid sequence that encodes a CAR that comprises a CD19 antigen binding domain, a CD8α hinge domain, a CD8α transmembrane domain, a 4-1BB costimulatory signaling region, and a CD3 zeta signaling domain (claim 90 and paragraph [0224]). They teach that the pharmaceutical composition comprising CAR-modified T cells can be in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients (paragraph [0222]). They also teach that modified T cells are expanded to therapeutic levels and are administered to a patient diagnosed with cancer as a method of treating a cancer associated with an elevated expression of a tumor antigen (Figure 11 and paragraphs [0020], [0031] and [0227]) and wherein said modified T cells can be administered in conjunction with any number of relevant treatment modalities, or used in combination with chemotherapy, radiation, anticancer agents including CAMPATH and fludarabine (paragraph [0227]).
June et al. even further teaches that the CAR can be engineered to target a tumor antigen of interest by way of engineering a desired antigen binding moiety that specifically binds to an antigen on a tumor cells, wherein tumor antigens include Her2/neu, TRP-1 and EGFRvIII (paragraphs [0129], [0130], [0133] and [0134]). They teach that the antigen binding moiety in the CAR can target a tumor antigen for the purpose of treating cancers, including solid cancers such as but not limited to breast cancer, lung cancer, ovarian cancer and prostate cancer (paragraphs [0199] and [0202]).
Guo et al. teaches that a fusion protein comprising interleukin-10–Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy (ACT), leading to eradication of established solid tumors and durable cures in the majority of treated mice (Abstract). They teach that CAR-T cells that targeted human HER2 responded to IL-10-Fc treatment by exhibiting enhanced oxygen consumption rate (OCR), proliferation and killing efficiency against targeted human cancer cell lines (Fig. 6a-c). They also teach that IL-10–Fc potentiates ACT therapy comprising HER2 CAR T cells to eradicate established tumors in multiple mouse models with durable protection (Figure 5a-5i). As taught by Tschumi et al., the HER2-targeting CAR of Guo et al. comprises an scFv fragment (Figure 1A and Pg 6 column right first full paragraph lines 3-6).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a T cell that constitutively expresses and secretes a IL-10 fragment and also expresses a CAR as taught by Mohseni et al. and substituting the anti-HLA-A2 scFv which is the extracellular antigen recognition domain of the CAR taught by Mohseni et al. with the anti-CD19 scFv of SEQ ID NO: 20 for the CAR as taught by June et al. because June et al. teaches that CD19 is an attractive tumor target for B cell malignancies; and because Guo et al. teaches that human CAR T cells adjuvanted by IL-10 completely eradicated tumors and led to durable cures in treated mice. In addition, by making engineered CAR T cells that express a recombinant IL-10 fragment themselves, said T cells have the advantage of delivering IL-10 directly to the tumor site, drastically reducing systemic exposure of IL-10 that is otherwise administered systemically, thus minimizing toxic side effects. These are examples of (B) Simple substitution of one known element for another to obtain predictable results; (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to instant claim 16, it would have been obvious to perform a combined method of making a T cell that constitutively expresses and secretes a IL-10 fragment as taught by Mohseni et al. wherein the T cell is autologous as taught by June et al. because autologous T cells are T cells retrieved from the same subject which have the advantage of being “self” which translates to no immune rejection, longer survival, and high clinical safety, as well as having a proven track record since most approved CAR-T cell therapies are autologous.
With regards to instant claim 24, it would have been obvious to perform a combined method of making a pharmaceutical composition comprising a therapeutically effective amount of immune cells as taught by June et al., wherein the immune cells are T cells that constitutively express and secrete a IL-10 fragment as taught by Mohseni et al. because formulating CAR-T cells into a controlled pharmaceutical composition has the advantage of standardization of a complex "living drug" to ensure precise dosing, stability, and safety during delivery.
With regards to instant claims 25 to 28, it would have been obvious to perform a combined method of making said pharmaceutical composition as taught by June et al. and Mohseni et al. described in the paragraph above regarding instant claim 24, and further comprising at least one additional therapeutic agent or therapy that is an anticancer agent or chemotherapy as taught by June et al. because tumors utilize multiple pathways to evade the immune system and maintain survival, as such combination cancer therapy has the advantage of acting as dual or multiple, coordinated attacks to maximize tumor eradication synergistically. In addition, a pharmaceutical composition comprising said components together would deliver treatments simultaneously at the same time, facilitating ease of administration and reducing multiple systemic administrations.
With regards to instant claims 29 and 32, it would have been obvious to perform a combined method of treating cancer in a subject in need thereof, including breast cancer, lung cancer, ovarian cancer and prostate cancer as taught by June et al., comprising administering the pharmaceutical composition of the combined method of June et al. and Mohseni et al. described in the paragraph above for instant claim 24, because June et al. teaches that CAR T cells that can specifically recognize a tumor antigen can be administered at effective therapeutic levels as a method for treating a cancer associated with an elevated expression of said tumor antigen and further because Guo et al. teaches that human CAR T cells adjuvanted by IL-10 completely eradicated tumors and led to durable cures in treated mice.
With regards to instant claims 30 and 31, it would have been obvious to perform a combined method of treating a cancer, or of enhancing antitumor activity, in a subject in need thereof, the method comprising (i) genetically engineering native T cells from the subject as taught by June et al., with a recombinant construct encoding an IL-10 fragment as taught by Mohseni et al. and with a second recombinant construct encoding a CAR targeting a tumor antigen as taught by June et al. which recognizes CD19; (ii) expanding said engineered T cells ex vivo as taught by June et al.; and (iii) introducing said expanded engineered T cells into the subject also as taught by June et al. because of the advantage of being able to target a tumor antigen with the CAR expressing T cell that is augmented by the action of IL-10 which is expressed “in-house” from the same T cell for enhanced anti-tumor activity. This is because Guo et al. teaches that CAR-T cells that targeted human HER2 responded to IL-10-Fc treatment by exhibiting enhanced proliferation and killing efficiency against targeted human cancer cell lines and eradicated established tumors in multiple mouse models.
Claim Rejections - 35 USC § 103 (Second)
Claims 1-10, 12-13 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Mohseni et al. European Journal of Immunology 51, no. 10 (2021): 2522-2530; First Published Online 28 July 2021) as applied to claims 1-10 and 12-13 above and further in view of Rosenberg et al. (US20120213783A1 Date Published 2012-08-23).
The teachings of Mohseni et al. are discussed above.
Mohseni et al. do not specifically teach an immune cell wherein the transmembrane domain and hinge comprises instant SEQ ID NO: 6.
However, these deficiencies are made up in the teachings of Rosenberg et al.
Rosenberg et al. teaches CARs comprising an antigen binding domain, an extracellular hinge domain, a T cell receptor transmembrane domain, and an intracellular domain T cell receptor signaling domain (Abstract). They teach an extracellular hinge domain and transmembrane domain consisting of SEQ ID NO: 4 which comprises mouse CD8 extracellular hinge and transmembrane sequences (paragraph [0046]). Alignment of the transmembrane domain comprising instant SEQ ID NO: 6 with SEQ ID NO: 4 as taught by Rosenberg et al. showed that the latter sequence is an exact match with instant SEQ ID NO: 6 (see Alignment 3 below).
Alignment 3: Alignment of instant SEQ ID NO: 7 (top) with SEQ ID NO: 11 as taught by Huang et al. (bottom)
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a T cell that comprises a recombinant construct encoding a IL-10 fragment linked to a recombinant construct encoding a CAR containing a CD28 transmembrane domain as taught by Mohseni et al. and substituting the CD28 transmembrane domain as taught by Mohseni et al. with the CD8 extracellular hinge and transmembrane sequences of SEQ ID NO: 4 as taught by Rosenberg et al. because this amino acid sequence performs the same function of a transmembrane domain in a CAR construct as the CD28 transmembrane domain taught by Mohseni et al. These are examples of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (Third)
Claims 1-10, 12-13 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Mohseni et al. European Journal of Immunology 51, no. 10 (2021): 2522-2530; First Published Online 28 July 2021) as applied to claims 1-10 and 12-13 above and further in view of Huang et al. (WO2022164976A2 Date Published 2022-08-04; Priority Data: Provisional 63/142,158 filed on 27.01.2021 and Provisional 63/219,620 filed on 08.07.2021).
The teachings of Mohseni et al. are discussed above.
Mohseni et al. do not specifically teach do not specifically teach an immune cell wherein the intracellular T cell activation domain of CD3 comprises instant SEQ ID NO: 7.
However, these deficiencies are made up in the teachings of Huang et al.
Huang et al. teaches recombinant cells expressing CARs comprising CD3zeta with the amino acid sequence of SEQ ID NO: 11 (paragraph [0095] and Fig 28A). Alignment of the intracellular T cell activation domain of CD3zeta comprising instant SEQ ID NO: 7 with SEQ ID NO: 11 as taught by Huang et al. showed that the latter sequence is an exact match from residues 2 to 114 with instant SEQ ID NO: 7 (see Alignment 4 below).
Alignment 4: Alignment of instant SEQ ID NO: 7 (top) with SEQ ID NO: 11 as taught by Huang et al. (bottom)
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a T cell that constitutively expresses and secretes a IL-10 fragment and also expresses a CAR as taught by Mohseni et al. and substituting the intracellular domain of the CAR as taught by Mohseni et al. for the CD3zeta domain of SEQ ID NO: 11 as taught by Huang et al. because this amino acid sequence performs the same function of intracellular activation domain in a T cell as the CD3zeta signaling domain taught by Mohseni et al. in Figure 1A (see above Figure 1).
In addition, by making engineered CAR T cells that express a recombinant IL-10 fragment themselves, said T cells have the advantage of delivering IL-10 directly to the tumor site, drastically reducing systemic exposure of IL-10 that is otherwise administered systemically, thus minimizing toxic side effects. These are examples of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Allowable Subject Matter
The amino acid sequence of the scFv recognizing HER2 comprising SEQ ID NO: 2 is free of prior art.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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