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 .
Claims 1-19 and 26 are pending. No Requirement for Restriction/Election was mailed in this application.
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. This application is the national stage of PCT/US2022/019436 filed on 9 March 2022, which claims the benefit of US Provisional Application No. 63/158,642 filed on 9 March 2021.
Claims 1-19 and 26 have an effective US filing date of 9 March 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 15 November 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification (pages 39-42) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." The listing on pages 39-42 does not correspond with the references cited on the IDS. Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
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 1-19 and 26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 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-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 7-9 are rejected for recitation of intended result/effect without conferring any structural, material, or manipulative difference on the scope of the claim. Claim 1 recites “wherein the antigen presenting cells have been genetically modified to express a chemokine”; claim 7 recites, “wherein the APC is genetically modified to reduce or prevent immune suppression by the subject”; claim 8 recites “wherein the APC is genetically modified to increase expression of MHC”; and claim 9 “wherein the APC is genetically modified to increase expression of one or more co-stimulatory molecules”. First, the terms “reduce” and “increase” in claims 7-9 are relative terms that render these claims indefinite. The terms are not defined by the claim, nor does the specification provide a standard for ascertaining the requisite degree. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Secondly, regarding claims 1 and 7-9, it is unclear what genetic modifications are encompassed by these claims, that would fulfill the functional requirements of the claims. Lastly, it is unclear whether or not assessing, for examples, chemokine expression (claim 1), reduced immune suppression (claim 7) or increased expression of MHC (claim 8) are required for infringement because the methodology is implicit but there are no active method steps. Absent active method steps, it is unclear how these claims further limit the scope of the parent claim. Since the scope of claim 1 is indefinite, this rejection affects the scope of all depending claims. For purposes of applying prior art, claims 7-9 will read upon the same material elements of instant clam 1, namely APCs that have been modified to express a chemokine.
MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim’ and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim” (emphasis added). Since these claims fail to meet all (3) criteria set forth in MPEP 2173.05(g), then Claims 1-19 and 26 are rejected.
Claims 19 and 26 are further indefinite wherein they recite a transgene “for expressing at least one chemokine.” Claim 19 is directed to a product invention but this limitation fails to impose a material/structural limitation upon that product. Rather, the claims an element by what it does (“for expressing..”) instead of what it is.
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.
Claims 1-5, 7-12, 16-19, 26 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al. Vaccine, 27: 6210-6216, 2009 in view of Wood and Sehgal, Ultrasound Med Biol., 41(4):905-928, 2015.
Regarding claim 1 and 7-9, The Jiang et al. prior art teaches a method of treating a brain cancer comprising administering to the patient an effective amount of antigen presenting cells (APCs) that have been modified to express a chemokine. The method of Jiang et al. uses glioma lysate-pulsed dendritic cells (DCs) in combination with plasmid DNA vector encoding the gene for murine IP-10 (a.k.a. CXCL10 of the instant claims). As stated in the rejection under 112(b) above, since claims 7-9 do not materially further limit the APCs of claim 1, then the cells of claims 7-9 are taught by the APCs of Jiang as well.
Regarding claims 2 and 3, Jiang et al. treat dendritic cells with a vector encoding the chemokine CXCL10, which teaches the CXCL10 of the claims.
Regarding claim 4, Jiang et al. teach intra-tumoral injection (abstract) but a person having ordinary skill in the art of administering to intracranial tumors (see pg. 6211 at bullet 2.5) would have been able to perform intravenous injection without undue further experimentation. Thus, the intravenous injection of the instant claim is obvious in view of the teaching of Jiang and routine experimentation.
Regarding claims 10 and 11, the method of Jiang et al. teaches antigen presenting cells (APCs) that are allogenic, meaning from the same species specifically mouse (see pg. 6211 at bullet 2.3). While the prior art does not necessarily teach autologous (as defined as “from same individual”) APCs, the reference does discuss DC-based immunotherapy in humans where autologous cells are preferred (pg. 6214, last paragraph). Therefore, the prior art teaches allogenic administration and renders obvious autologous administration.
Regarding claim 12, the APCs utilized in the methods of Jiang et al. are the dendritic cells of the instant claim (Abstract).
Regarding claim 16, the method of Jiang et al. is an art-accepted model for the glioma of the instant claim (see Abstract).
Regarding claim 17 and 18, the method of Jiang et al. pulse the DCs with glioma lysate that has previously been shown to have anti-tumor effects (pg. 6210, last full sentence). Thus, the prior art teaches methods further comprising administering a further anti-cancer therapy to the patient, as claimed. While this treatment constitutes a chemotherapy as recited in instant claim 18, the reference further discloses that the treatment has anti-angiogenic benefits, specifically, d “reduced neovascularization” of the tumor (Abstract).
Regarding claims 19, 26 and 29, the Jiang prior art teaches isolated DCs that are pulsed with a vector that contains a gene (“transgene” of the instant claim) for expressing at least one chemokine, namely, CXCL10 (see pg. 6211 at bullets 2.1 and 2.5). The methods then teach compositions comprising these DCs and vectors and inoculation of these cells (pg. 6211 at bullet 2.5), which teaches the administering of instant claim 29.
The only element of instant claim 1 that Jiang et al. does not teach, is the “ultrasound blood brain barrier disruption”; as well as the low-intensity pulsed ultrasound of instant claim 5.
The Wood and Sehgal prior art reference, however, remedies this deficiency. Wood and Sehgal teach, “insonation of neoplasms with low-intensity ultrasound is easy to perform as it does not require a focused beam (that must be accurately located), the apparatus is relatively inexpensive, the bioeffects in adjacent normal tissues are commonly believed to be minimal, and it is possible to easily target sensitizing or chemotherapeutic molecules and microbubbles located within the lumens of the tumor neovasculature” (pg. 2, third paragraph). The authors teach low-intensity ultrasound enhances the delivery of agents to the cancer cells whilst minimizing the cytotoxic effects in the contiguous normal tissue (pg. 4, last paragraph).
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalence for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). This case law applies to the instant claims because they combine two elements each of which were known in the art prior to filing to be beneficial for cancer treatment, namely, dendritic cells (DCs) with plasmid DNA vector encoding CXCL10 and low-intensity ultrasound.
Therefore, the invention of claims 1-5, 7-12, 16-19, 26 and 29 is rendered obvious in view of the combined elements of the prior art references.
Claims 6 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al. taken with Wood and Sehgal, as applied to claims 1-5, 7-12, 16-19, 26 and 29 above, and further in view of Schetters et al. J for ImmunoTherapy of Cancer, 2020; 8:e000588.
The teachings of Jiang et al. taken with Wood and Sehgal, as they pertain to the invention of claims 1-5, 7-12, 16-19, 26 and 29 is outlined in the rejection above.
Neither Jiang et al. nor Wood and Sehgal teach subjects that have previously failed immunotherapy (instant claim 6); the administration of a checkpoint inhibitor (instant claim 13); wherein the inhibitor is an anti-PD-1 antibody (instant claim 14); and wherein the anti-PD1 antibody comprises nivolumab, pembrolizumab, pidilizumab, AMP-223, AMP-514, cemiplimab, or PDR-001 (instant claim 15). The Schetters et al. prior art reference remedies these deficiencies.
Regarding claim 6, Schetters teaches: “PD1 immune checkpoint blockade (αPD1 ICB) has shown unparalleled success in treating many types of cancer. However, response to treatment does not always lead to tumor rejection” (Abstract). This teaches subjects that have failed previous immunotherapy as required by instant claim 6.
Regarding claims 13 and 14, the Schetters prior art teaches: “the mode of action for PD-1 blocking antibodies has been proposed to be by reducing the brake of PD1 on the costimulatory capacity of CD28. The co- stimulatory receptor CD28 can be triggered by the members of the B7 family of immunoglobulin superfamily, including CD80 and CD86. Since CD80 and CD86 are primarily expressed by antigen-presenting cells (APCs), successful αPD1 ICB is now thought to rely on the presence of CD80/CD86-expressing APCs” (paragraph bridging pages 1-2). Thus, the prior art discloses Check Point Inhibition for the treatment of cancer and specifically discloses the anti-PD1 antibody of instant claim 14.
Regarding claim 15, while the prior art utilizes RMPI-14(see page 2, paragraph bridging columns) rather than one of the listed antibodies of the claim, it discloses this antibody as an anti-PD-1 antibody and recognizes a common mode of action among all PD-1 blocking antibodies (paragraph bridging pgs. 1-2) . In KSR International Co. v. Teleflex, Inc., the Supreme Court has stated that where there is a “pressure to solve a problem and a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense” (KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). In the instant case, the problem to be solved is PD-1 inhibition by an antibody, and the art demonstrates that there are a finite number of antibodies that fulfill this function. A person having ordinary skill would have good reason to pursue any of the known options without having to perform undue further experimentation. A skilled artisan would understand that these anti-PD-1 antibodies could be used interchangeably with predictable success.
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, that the methods as taught by Jiang et al. could be used in combination with the anti-PD-1 antibodies taught by Schetters. Motivation to combine these teachings is explicit in the Schetters reference wherein it states: We show, in responding mouse tumor models, that monocyte-derived dendritic cells express high levels of costimulatory molecules and are correlated with effector tumor-infiltrating lymphocytes in the tumor microenvironment (TME) after anti-PD1 therapy (Abstract Results). Thus, a person having ordinary skill would have been motivated to combine all of these therapies (CXCL10 gene primed DCs as taught by Jiang, low-intensity pulsed ultrasound (LIPU) as taught by Wood and Sehgal, and anti-PD-1 antibodies as taught by Schetters) because the separate references teach each to be effective alone at treating cancer.
Therefore, the invention of claims 6 and 13-15 is obvious in view of the combined teaching of the prior art. No further experimentation would have been required in order to combine elements that were each taught to be effective treatments for cancer, into a single therapy.
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/ Examiner, Art Unit 1675