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 instant application is in response to the papers filed on January 17, 2024 of which claims 1-20 were filed, and are currently pending. Therefore, claims 1-20 are currently under examination to which the following grounds of rejection are applicable.
Priority
Acknowledgement is made of applicant’s claim of benefit under 35 U.S.C. 119(e) of prior-filed provisional application 63/439,526, filed on January 17, 2023.
Specification
The abstract of the disclosure is objected to because the section incorrectly recites, “interleukin=12” as opposed to “interleukin-12”.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 6, 11-13 are objected to because of the following informalities:
Claim 6 is objected to because the recited abbreviation(s), “GM-CSF” should be spelled out at the first encounter in the claims.
Claim 11 is objected to because the recited abbreviation(s), “HLAII” should be spelled out at the first encounter in the claims.
Claim 12 is objected to because the recited abbreviation(s), “DEC-205” should be spelled out at the first encounter in the claims.
Claim 13 is objected to because the recited abbreviation(s), “TGF-beta” should be spelled out at the first encounter in the claims. Appropriate corrections are required.
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.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more.
Claim 1 is directed to a composition useful for stimulating an immune response to cancer comprising exosomes produced by dendritic cells expressing survivin or parts of the survivin gene, wherein said dendritic cells are derived from a cell type that was dedifferentiated into immature cells which are subsequently used to generate a dendritic cell population, wherein during said immature phase various immunomodulatory modifications have been made to said immature cells, furthermore wherein said modified immature cells are expanded to generate a master cell bank and subsequently said immature cells are differentiated to dendritic cells and said dendritic cells are utilized as a source of exosomes.
The USPTO's current eligibility guidance is found in Section 2103 through 2106.07 of the Manual of Patent Examining Procedure (MPEP).
In view of the Subject Matter Eligibility Test recited in MPEP 2106, with regard to Step 1, the claims are directed to the statutory category of a composition of matter.
Regarding Step 2A prong 1, the claim recites a judicial exception in particular a product of nature. Regarding prong two, the claim does not recite any additional elements that integrate the judicial exception, i.e. product of nature, into a practical application because the additional limitations are well- understood, routine and conventional in the field. Khan et al. (Histol Histopathol. 2015 January ; 30(1): 43–50) describes the function of exosomes with relation to cancer, by stating, “Recent work suggests that the use of exosomes in immunotherapy may stimulate the immune system to recognize and kill cancer cells and thus could form an attainable basis for the development of novel cancer vaccines (Kovar et al., 2006; Tan et al., 2010; Wang et al., 2014a).” (p 4, par, 3). The claim merely states the composition as being exosomes derived from dendritic cells (DCs). Furthermore, the claimed exosomes are not structurally different from the ones found in nature despite claiming a process by which they are made. The process by which the composition is obtained does not weigh on the structure of the composition, unless it is readily apparent that the process has produced a different composition or evidence is provided that demonstrates the method of production has resulted in an altered product.
Regarding Step2B, the claims do not include additional elements, or a combination of additional elements that are sufficient to amount to significantly more than the judicial exception. The examiner is recommending providing evidence that the claimed exosomes are markedly different than what is found in nature, and furthermore amending the claim to include such limitations. As described above, the inclusion of product-by-process limitations does not overcome this rejection as the structure of the product is expected to be identical to exosomes found naturally.
In conclusion, based on the two-part test, claims 1-20 are rejected under 35 U.S.C. 101.
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 1-20 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.
The term “useful” in claim 1 is a relative term which renders the claim indefinite. The term “useful” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, there are no limitations provided to determine the scope as to what composition is considered useful for stimulating an immune response to cancer.
The recitation of “parts of the survivin gene,” as recited in claim 1 is indefinite because it is not clear what constitutes this limitation. It is not clear if the claim scope comprises coding and/or non-coding regions (e.g. regulator regions, introns), specific regions of the coding region, or a specific sequence similarity in relation to the survivin gene. Altogether, the limitation is not definite for not clearly pointing out the survivin gene sequence(s) that are encompassed.
Claim 1 is indefinite in the recitation of “wherein during said immature phase various immunomodulatory modifications have been made to said immature cells,” as it is not clear what constitutes various immunomodulatory modifications.
Claim 1 recites the limitation "said immature phase" in line 4-5. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 is indefinite in the recitation of “by administration of siRNA sequence comprising of (sense, GCAACAACGCCAUCUAUGA (SEQ ID NO: 1); antisense, UCAUAGAUGGCGUUGUUGC (SEQ ID NO: 2)” because the scope of the claim is unclear. Are the sense and antisense both included or are in the alternatie?
Claim 15 is indefinite in the recitation of “wherein said dendritic cells are pulsed with a survivin peptide” based on dependency to claim 1, which states “dendritic cells expressing survivin or parts of the survivin gene”, and therefore it is unclear if the claim 15 limitation is in addition to the survivin gene expression recited in claim 1. If the limitation presented in claim 15 is intended to be the same survivin gene recited in claim 1, then the claim remains indefinite due to claim 1 reciting a gene which is different than the amino acid/peptide recited in claim 15.
Claim 18 is indefinite in stating that SEQ ID NO: 5 is a survivin peptide, despite sequence analysis revealing it is rather the PADRE peptide (Pan-DR epitope) a synthetic peptide designed to bind to MHC class II molecules as evidenced by Halkier et al. (WO 2001/05820-A2). Halkier teaches SEQ ID NO: 13 that is 100% identical to instant SEQ ID NO: 5, and is described accordingly as an artificial T-cell epitope that binds to MHC class II molecules (p 25, par 2-3). Altogether, the scope of claim 18 is indefinite for describing the pulsing with a survivin peptide claimed as SEQ ID NO:3, yet this sequence does not encode survivin.
Claim 20 is indefinite for reciting both a composition and a method in the same claim as seen in reciting “The composition of claim 19,” and “wherein said exosomes are administered as a cancer therapeutic”, and therefore the scope of the claim is not clear.
Claim Rejections - 35 USC § 102/103
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 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 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 1-20 are rejected under 35 U.S.C. 102(a)(1)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Taylor et al. (US 8,455,188 B2) in view of Oliveira et al. (Stem Cells and Development. 2022;31(9-10):207-220).
The independent claims recites a product-by-process.
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) MPEP 2113.
The claims are directed to “composition…comprising exosomes…” As such, overlap between the exosomes produced by dendritic cells not generated in the claimed manner would still read on the claim so long as some of the exosomes (2 or more) are the same or not patentably distinct from the prior art exosomes.
Regarding claim 1, Taylor teaches a composition useful for stimulating an immune response to cancer comprising exosomes (col 1, ln 21-27) produced by dendritic cells (DCs) (col 7, ln 27-40) that express survivin (“The exosomes of the presently disclosed subject matter are well-suited for producing antigens that can stimulate desirable immune responses in subjects because they are produced by cells…As non-limiting examples, the cancer cell antigen can be…survivin” (col 7, ln 45-62)).
Taylor doesn’t completely describe the process for obtaining the exosomes as it does not teach the remaining product-by-process limitations. However, it appears the instant product is the same as the product taught by Taylor, and thus anticipates the subject matter.
In reference to the remaining limitations that concern methods of making the DCs for which the claimed exosomes are derived, these limitations are considered product-by-process limitations. Therefore, despite Taylor not clearly teaching “dendritic cells are derived from a cell type that was dedifferentiated into immature cells which are subsequently used to generate a dendritic cell population, wherein during said immature phase various immunomodulatory modifications have been made to said immature cells, furthermore wherein said modified immature cells are expanded to generate a master cell bank and subsequently said immature cells are differentiated to dendritic cells and said dendritic cells are utilized as a source of exosomes”, Taylor is expected to teach claim 1 based on teaching the entirety of the claimed composition.
However, even if Taylor’s exosomes and the claimed exosomes are not the same and there is, in fact, no anticipation, Taylor’s teachings would nevertheless have to one of ordinary skill in the art at the time the invention was claimed rendered obvious the claimed exosomes based on the process of obtaining dendritic cells of which the exosomes are derived as being well known in the art as described in Oliveira et al..
Oliveira teaches the generation of dendritic cells beginning with somatic cells isolated from a subject which are then reprogrammed into human induced pluripotent stem cells (hiPSCs). These cells, which are being considered immature, are differentiated directly to dendritic cells or monocytes then dendritic cells (Fig. 1; p 213, col 2, par 4).
In reference to the limitation, “furthermore wherein said modified immature cells are expanded to generate a master cell bank”, this is being understood as an intended use, in particular an intended use for the immature cell types of which is not concerned with the structure of the claimed composition.
Thus, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the references, especially in the absence of evidence to the contrary.
Regarding claim 2-3, the rejection above to claim 1 describes that Oliveira teaches dendritic cells (DCs) are generated from human induced pluripotent stem cells (hiPSCs) (Fig. 1).
Regarding claims 4-5, the rejection above to claim 1 describes that Oliveira teaches pluripotent stem cells are differentiated into monocytes which are then differentiated to dendritic cells (p 213, col 2; Table 1).
Regarding claim 6, Oliveira teaches pluripotent stem cells are differentiated into monocytes by culture in GM-CSP and IL-4 (p 209, col 1; p 213, col 2; Table 1, column 9).
Regarding claims 7-12, the dendritic cell markers of CD11C, CD40, CD80, CD86, HLAII, DEC-205 (CD205), respectively, are taught by Oliveira as listed on Table 1 column 4.
Regarding claims 15 and 19, Taylor teaches dendritic cell derived exosomes pulsed with survivin (col 7, ln 37-62).
Regarding claim 20, the rejection under 35 USC 112(b) above describes the scope of the claim not being clear based on being directed to a composition, yet reciting a method of treatment. Regardless, Taylor teaches the composition recited in claim 1, and furthermore teaches a method of treatment of cancer by administering exosomes as a therapeutic (col 4, line 25-28).
Claim Rejections - 35 USC § 103
Claims 1, 4, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (US 8,455,188 B2) in view of Oliveira et al. (Stem Cells and Development. 2022;31(9-10):207-220) as applied to claims 1 and 4 above, and further in view of Tie et al. (Molecular biomedicine 3.1 (2022): 45) and Naito et al. (US 2008/0113351 A1; STIC Search Result).
Regarding claims 1 and 4, the disclosure of Taylor in view of Oliveira is applied as in the rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 13 and 14, Taylor in view of Oliveira teach dendritic cell derived exosomes, and the process of differentiation of stem cells to dendritic cells involving a monocyte cell type stage as described above. The references do not teach silenced expression of TGF-β (claim 13), and the respective siRNA sequence for silencing of TGF-β (claim 14).
Tie et al. describes that targeting of TGF-β with antisense oligonucleotides as a known strategy to treat cancers, and being effective (p 9, col 1; Fig. 5). The review describes two examples for treating select cancers, Trabedersen (AP12009), a synthetic phosphorothioate antisense oligodeoxynucleotide blocking the production of TGF-β2; and ISTH0036, an antisense oligonucleotide selectively targeting TGF-β2 signals, in addition to other TGF-β antisense oligonucleotides (p 18, col 2).
In reference to instant SEQ ID NOs: 1 and 2 of claim 14, Naito et al. teaches antisense technology via RNAi (abstract), and sequences identical to the claimed sequences as seen in Fig. 1 and 2 below for SEQ ID NOs 1 and 2, respectively. It is noted that Naito also teaches instant SEQ ID No: 2 since it is the same sequence as instant SEQ ID No:1, but the reverse complement as seen below in Fig. 2. This is reflected in the STIC sequence searches that are provided herein with the Office Action.
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the monocytes/dendritic cells taught by Taylor in view of Oliveira to incorporate siRNA for TGF-beta as taught by Tie and Naito because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating a siRNA targeting TGF-beta in the monocytes/dendritic cells would have led to the predictable result of treating cancer based on Tie teaching this outcome, and therefore there would a similar expected outcome when using the derived exosomes from these cells for treating cancer.
Additionally, the instant claims are directed to a composition, particularly dendritic cell-derived exosomes, and therefore claims 13-14 are considered product-by-process limitations. The claims are concerned with methods of making the monocytes/dendritic cells, and therefore it remains unclear how the structure of the exosomes are related.
Fig. 1:
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Fig. 2:
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Claims 1, 5, 12, 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (US 8,455,188 B2) in view of Oliveira et al. (Stem Cells and Development. 2022;31(9-10):207-220) as applied to claims 1, 5, 12, 15 above, and further in view of Gillies et al. (US Pub. No. 2007/0104689-A1; STIC search result) and Halkier et al. (WO 2001/005820-A2).
Regarding claims 1, 5, 12, and 15, the disclosure of Taylor in view of Oliveira is applied as in the rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 16-18, Taylor in view of Oliveira teach dendritic cell derived exosomes, and the process of differentiation of stem cells to dendritic cells involving a monocyte cell type stage as described above. Moreover, as described in the claim 15 rejection above, Taylor teaches pulsing dendritic cell-derived exosomes with pulsed survivin peptide.
The references do not teach the survivin sequences recited in claims 16-18, SEQ ID Nos: 3-5, respectively.
Gillies teaches SEQ ID NO: 10 that is 100% similar to instant SEQ ID NOs 3 and 4 as seen in Fig 3 and 4 below. Result # 3, Duplicate #1 for SEQ ID NO: 3, and Result # 7, duplicate #1 for SEQ ID NO: 4. STIC Sequence Search Results provided with the Office Action.
Fig. 3: Sequence Alignment of instant SEQ ID NO: 3 to Gillies SEQ ID NO: 10:
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Fig. 4: Sequence Alignment of instant SEQ ID NO: 4 to Gillies SEQ ID NO: 10:
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Halkier teaches SEQ ID NO: 13 that is 100% similar to instant SEQ ID NO: 5 that encodes
the PADRE peptide (Pan-DR epitope) a synthetic peptide designed to bind to MHC class II molecules as seen in Fig. 5 below (p 25, par 2-3).
Fig. 5: Sequence Alignment of instant SEQ ID NO: 5 to Halkier SEQ ID NO: 13:
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It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have pulsed the dendritic cell-derived exosomes with survivin as taught by Taylor
in view of Oliveira with the peptides taught by Gillies (in relation to SEQ ID NOs: 3 and 4) and Halkier (in relation to SEQ ID NO: 5) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. In particular, these peptide sequence were known in the art and pulsing of the claimed exosomes with survivin peptides was additionally known, and therefore the use of these particular survivin peptide sequences would be an obvious step, and furthermore there would be a reasonable expectation that such sequences would be successfully incorporated based on this process being conducted as taught by Taylor.
Additionally, the instant claims are directed to a composition, particularly dendritic cell-derived exosomes, and therefore claims 13-14 are considered product-by-process limitations. The claims are concerned with methods of making the monocytes/dendritic cells, and therefore it remains unclear how the structure of the exosomes are related to pulsed dendritic cell. The claims should recite the derived exosomes as comprising survivin, if supported by the disclosure.
Conclusion
Claims 1-20 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634