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 Status
The Amendment filed on 09Apr2024 is acknowledged in which claim(s) 1-38, 42, 44-45, 50, 52, 54, 56-57, 59-67, 69-100, 104, and 106-107 were canceled by Applicant.
Claim(s) 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105, and 108-110 is/are currently pending and presented for examination on the merits.
Claim Objections
Claim(s) 39 (and dependent claims 40-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105, 108-110) is objected to because of the following informalities: “cell- derived” in line 2 should be “cell-[[ ]]derived”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 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.
Claim(s) 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105, and 108-110 is/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.
Regarding claim(s) 39-41, 43, 46-48, 53, 55, 58, 68, 101-103, 105, the phrase “anucleate cell-derived vesicles” in claim(s) 39, 43, and 105 renders the claims indefinite. Specifically, it is unclear if the phrase means (1) a vesicle that is cell-derived and is also anucleate; (2) a vesicle that is derived from an anucleate cell; (3) or something else. For the purposes of compact prosecution the phrase is considered to mean “vesicles derived from anucleate cells”. This rejection may be overcome by amending claim(s) 39, 43, and 105 (1) as described above or (2) to otherwise clearly recite the limitation(s) of the claimed invention. Dependent claim(s) 40-41, 46-48, 51, 53, 55, 58, 68, and 101-103 can overcome this rejection by amending claim(s) 39, 43, and 105 as described above.
Regarding claim(s) 39-41, 43, 46-49, 51, 53, 55, 58, 68, 101-103, 105, 108-110, the phrase “anucleate cell-derived vesicles comprise a mutated RAS intracellularly” in claim 39; “introducing the mutated Ras antigen to the anucleate cell-derived vesicles intracellularly” in claim 101, and/or “mutated Ras antigen and the adjuvant to anucleate cell-derived vesicles intracellularly” in claim 105 renders the claims indefinite. The instant disclosure does not define “intracellularly”, so the term is given the common meaning in the art of “within a cell”. Specifically, a vesicle is not a cell, and therefore it is unclear if “intracellularly” in the phrases recited above means (1) within the cell from which the vesicle is derived, (2) within the vesicle itself, or (3) something else. In the interest of compact prosecution, the term ‘intracellularly’ within each phrase is considered to mean ‘within the vesicle’. This rejection may be overcome by amending claims 39, 101, and 105 to clearly recite the claimed limitation(s). Dependent claim(s) 40-41, 43, 46-49, 51, 53, 55, 58, 68, 102-103, and 108-110 can overcome this rejection by amending claims 39, 101, and 105 as described above.
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 therefor, subject to the conditions and requirements of this title.
Claim(s) 39-41 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (natural phenomenon) without significantly more.
Claims 39-41 are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a process (method) which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards the natural phenomenon “anucleate cell-derived vesicles, wherein…vesicles comprise mutated RAS antigen intracellularly”. In the broadest reasonable interpretation of the claim(s) this includes naturally occurring anucleate cell derived vesicles containing mutant RAS antigen.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. While claim 39 recites “anucleate cell-derived vesicles comprise a mutated Ras intracellularly”, this does not integrate a judicial exception into a practical application. Specifically, the instant claimed composition is not a practical application, but rather generally links the judicial exception to a particular technological environment (see MPEP § 2106.05(h)).
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. The prior art teaches erythrocytes (e.g., anucleate cells) commonly form vesicles comprising proteins of the parent cell, see Pollet et al. (Biomolecules, 2018, 8, 94.; e.g., abstract; 4, 5.3.2; figs. 1-4; tbl. 1) and further that erythrocyte cancers comprise RAS mutants, see Iacobucci et al. (Nature Genetics, Vol 51, APRIL 2019, 694–704; e.g., pg. 699, “targetable signaling mutations in AEL”; fig 2A). Given the knowledge in the prior art, vesicles from anucleate cells containing mutated Ras are considered to be a naturally occurring phenomenon and therefore, do not amount to significantly more than the judicial exception that is claimed.
Claim(s) 40-41, which depend from claim 39, act to further limit the adjuvant of the composition to naturally occurring molecules (e.g., IFNy). The limitations do not amount to significantly more than the judicial exception.
As the instant claims 39-41 claim a composition for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found not to be drawn to eligible subject matter under 35 USC § 101.
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.
(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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 39 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Iacobucci et al. (Nature Genetics , Vol 51, APRIL 2019, 694–704; hereinafter “Iacobucci”), as evidenced by Pollet et al. (Biomolecules, 2018, 8, 94.;hereinafter “Pollet”).
Regarding instant claim(s) 39, Iacobucci teaches that erythrocyte cancers comprise RAS mutants [e.g., ., pg. 699, “targetable signaling mutations in AEL”; fig 2A]. Iacobucci further discloses results are from previously collected primary AEL samples [e.g., “Methods”]. As evidenced by Pollet, erythrocytes (e.g., anucleate cells) commonly form vesicles comprising proteins of the parent cell [e.g., ¶ ]. Therefore the primary AEL sample of Iacobucci would necessarily comprise vesicles comprising RAS mutants.
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.
Claim(s) 39-41 and 101-103 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0054192 A1 (hereinafter “US192”), in view of WO 2018/145020 A1 (hereinafter “WO020”).
Regarding instant claim(s) 39-41, 101-103, US192 teaches RBC EVs loaded with nucleic acid (e.g., DNA or RNA) for the treatment of cancer [e.g., title; abstract; ¶ 0002, 0007-0008, 0019-0025]. US192 further teaches that RBC EV mediated delivery of nucleic acids for the treatment of cancer because the natural biocompatibility thereof is generally non-toxic, and therefore reduces therapeutic cargo toxicity [e.g., ¶ 0003, 0005, 0008, 0043-0044]. US192 further teaches a method of making the RBC EVs comprising electroporating nucleic acid cargo into (e.g., “intracellularly”) the RBC EV [e.g., abstract; ¶ 0007, 0010, 0012-0015, 0019-0023, 0028-0038, 0044, 0049-0056].
US192 does not expressly teach (1) a composition comprising an RBC EV comprising Ras antigen, wherein (a) the composition further comprises a CpG oligodeoxynucleotide (ODN) adjuvant, or (b) the RAS is introduced into the RBC EV; or (2) a method for producing RBC EVs comprising mutant RAS and/or CpG adjuvant wherein the mutant Ras antigen is electroporated (e.g., introduced “intracellularly”).
Regarding instant claim(s) 39, 101, WO020 teaches KRAS peptide vaccine compositions and methods of use including treating cancer [e.g., title; abstract; ¶ 0007-0010]. WO020 further teaches the G12D and G12V KRAS mutants stimulate a robust immune response and can be used as vaccines to help a subject’s body fight cancer [e.g., ¶ 00105, 00114-00116, 00118, 00150]. Regarding instant claim(s) 40-41, 102-103, WO020 further teaches the KRAS vaccine composition further comprises an adjuvant [e.g., ¶ 0037, 0044-0045], and that the adjuvant is CpG CpG-containing oligonucleotide ODN 1826 [e.g., ¶ 0045].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the nucleic acid cargo of the RBC EVs loaded with nucleic acid as taught by US192, with the KRAS mutant vaccine and CpG adjuvant as taught by WO020, in the context of designing and developing a RBC EV loaded with nucleic acid for cancer therapy. A PHOSITA would have been motivated to substitute the nucleic acid cargo of the RBC EVs loaded with nucleic acid as taught by US192, with the KRAS mutant vaccine and CpG adjuvant as taught by WO020, because US192 teaches the base composition of the RBC EV loaded with nucleic acid cargo with reduced toxicity, both US192 and WO020 teach nucleic acid mediated cancer therapeutics, and WO020 further teaches KRAS vaccine with CpG ODN adjuvant (e.g., nucleic acids) are effective for treating cancer. There would have been a reasonable expectation of success for a PHOSITA to substitute the nucleic acid cargo of the RBC EVs loaded with nucleic acid as taught by US192, with the KRAS mutant vaccine and CpG adjuvant as taught by WO020, because US192 teaches the RBC-EV comprising nucleic acid cargo for cancer therapy, and WO020 teaches mutant KRAS vaccine and CpG ODN adjuvant as effective cancer therapeutics. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified composition of US192 and WO020 (see above) to include that (1) the RAS is introduced into the RBC EV; or (3) a method for producing RBC EVs comprising mutant RAS and/or CpG adjuvant wherein the mutant Ras antigen is electroporated (e.g., introduced “intracellularly”) as taught by US192 and/or WO020, because US192 and WO020 teach the base composition comprising KRAS vaccine and adjuvant for cancer therapy, US192 further teaches methods for producing the RBC EVs (e.g., via electroporation of cargo into vesicle). There is an expectation of success for a PHOPSITA to substitute the methods of making RBC EVs and/or the therapeutic target as taught of the modified RBC EV comprising mutated KRAS cargo as taught by US192 and WO020 (see above), with the methods of making RBC EVs (e.g., electroporation) as further taught by US192, because the base RBC EV comprising mutant KRAS is taught by US192 and WO020, US192 teaches additional method modifications thereto. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 43, 46-49, 51, 53, 55, 58, 68, 105, and 108-110 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0054192 A1 (hereinafter “US192”) and WO 2018/145020 A1 (hereinafter “WO020”), as applied to claim(s) 39-41 above, and further in view of WO 2017/008063 A1 (hereinafter “WO063”).
The teachings of US192 and WO020 as recited above for claim(s) 39-41 are applied herein.
Regarding instant claim(s) 55, WO020 further teaches the KRAS vaccine of the invention includes peptides, nucleic acid sequences encoding peptides and compositions containing one or more peptides that can be used to elicit an anti-tumor response in a subject [e.g., ¶ 0029], and that the KRAS vaccine is capable or driving immunogenic targeting multiple epitopes of the KRAS molecule [e.g., ¶ 0081].
US192 and WO020 do not expressly teach (1) a composition comprising an RBC EV comprising mutant Ras antigen, wherein (a) the RBCs are passed through a cell deforming constriction width to (i) about 20% to about 99% of the largest diameter of the cell, or (ii) about 1.8 to about 2.2 um, causing perturbations, and incubating antigen and adjuvant with perturbed cells to generate anucleate cell derived vesicles comprising mutant RAS; (b) the cell suspension is passed through multiple constrictions in series and/or in parallel; and (c) the mutated KRAS antigen elicits a response against KRAS antigens.
Regarding instant claim(s) 43, 46-7, 49, 51, 53, 55, 58, 68, 105, 108-109, WO063 teaches the delivery of materials into anucleate cells, with a focus on RBCs [e.g., title; abstract; ¶ 0004]. WO063 further teaches that RBC have unique structural and physiological features that make it difficult to load cargo into RBCs via conventional methods [e.g., ¶ 0005]. WO063 teaches methods to overcome the barriers to penetration of RBCs comprising passing an RBC cell suspension through a cell-deforming constrictions wherein the diameter of the constriction is about 20% to about 90% of the mean diameter of the input cells [e.g., ¶ 0006-0019], and incubating the cells in a payload-containing solution for a predetermined time before or after the cell passes through the constriction [e.g., ¶ 0012-0021]. Regarding instant claim(s) 48, 110, WO063 further teaches the input RBC cells are passed through multiple constrictions [e.g., ¶ 0044].
Further, it would have been obvious to a PHOSITA to modify the modified method of making RBC EVs comprising mutant RAS or mutant RAS and adjuvant as taught by US192 and WO020 (see above) to include (1) a composition comprising an RBC EV comprising mutant Ras antigen, wherein (a) the RBCs are passed through a cell deforming constriction width to about 20% to about 99% of the largest diameter of the cell, causing perturbations, and incubating antigen and adjuvant with perturbed cells to generate anucleate cell derived vesicles comprising mutant RAS, (b) the cell suspension is passed through multiple constrictions in series and/or in parallel, and (c) the mutated KRAS antigen elicits a response against KRAS antigens as taught by WO063 or WO020, because US192 and WO020 teach the base composition comprising RBC EV comprising mutant KRAS, WO063 teaches improved methods of introducing cargo through RBC membranes, , and WO020 further teaches how the vaccine works (e.g., by eliciting immune response against mutant KRAS). There is an expectation of success for a PHOPSITA to substitute the method of introducing cargo in the modified method of making RBC EVs comprising mutant KRAS as taught by US192 and WO020 with the improved methods of introducing cargo through RBC membranes as taught by WO063 and the KRAS target antigen(s) as further taught by WO020, because US192 and WO020 teach the base method of making RBC EVs comprising mutant KRAS, WO063 teaches improved methods of introducing cargo through RBC membranes, and WO020 teaches specific KRAS vaccine targets. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, in regard to the specific micrometer ranges of constriction (e.g., about 1.8 to about 2.2 um) as recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the constriction range(s) is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of constriction because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the art. Therefore, it would be conventional and within the skill of the art to identify operable and/or optimal constriction range(s). Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal constriction ranges. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that optimization is obvious.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643