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 .
The preliminary amendment filed 6/8/2023 has been received and entered into the application file. Claims 1, 4-14, 19-21, 35, 37, 38, 41 and 42 are pending, all of which have been considered on the merits.
Priority
Acknowledgement is made of Applicants’ claim for benefit as a continuation of PCT/US2021/029613 (filed 4/28/2021), which claims benefit of prior-filed US Provisional application 63/016,626 (filed 4/28/2020).
Drawings
The drawings submitted 10/14/2022 are objected to as they contain color images without a granted petition for acceptance of color images.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
Claim 41 is a product-by-process claim. It defines the composition by its method of production. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore if the product, as claimed, is the same or obvious over a product of the prior art (i.e. is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113.
In the instant case, the composition of claim 41 is interpreted as a composition comprising MSCs, wherein the MSCs:
contain one or more exogenous synthetic RNA molecules that encode for a reprogramming factor, and
have a protein secretion signature comprising:
an increased secretion of one or more proteins selected from [the list set forth at lines 8-13 of claim 1] compared to bone marrow-derived MSCs, and/or
decreased secretion of one or more proteins selected from IL-6, IL-8 and IL-4 compared to bone marrow-derived MSCs.
Claim 42 is drawn to a method comprising:
obtaining an MSC, having been made by a specific method, and having a specific protein secretion signature, and
administering an effective amount of the MSC substantially having the protein secretion signature to a patient in need thereof as therapy.
Under broadest reasonable interpretation, step (a) ‘obtaining’ does not require actively carrying out the derivation steps, but rather only requires obtaining (e.g. acquiring, selecting) the MSC. The manner in which the MSC is derived from an iPSC is considered a product-by-process limitation. The MSC ‘obtained’ in step (a) must have the physical and biochemical features of the MSCs of claim 41.
Claim Rejections - 35 USC § 112
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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1, 4-14, 19-21, 35, 37, and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims under rejection are drawn to methods involving an active step of “reprogramming induced pluripotent stem cells (iPSCs) into mesenchymal stem cells (MSCs),” wherein the reprogramming comprises “contacting an iPSC with one or more synthetic RNA molecules encoding a reprogramming factor”. However, the specification fails to disclose any specific synthetic RNA molecules encoding a reprogramming factor that would achieve reprogramming of an iPSC to an MSC. Rather, disclosure of use of reprogramming factors is limited to reprogramming non-pluripotent cells to iPSCs (see Fig 1; specification at Pg 20, ln 6 through Pg 23, ln 30; see Example 1 at Pg 55). The specific reprogramming factors recited in claim 19 are disclosed as effective to reprogram somatic cells (e.g. fibroblasts) into iPSCs (See, e.g., Pg 20, ln 6-13), not iPSCs into MSCs.
As of the effective filing date, it was known how to reprogram somatic cells to iPSCs using mRNA (See Warren et al, Cell Stem Cell, 2010; See Angel Thesis, 2011). It was also known to differentiate iPSCs to MSCs using various cell culture protocols (See Chow et al, Stem Cell Research, 2017; Lian et al, Circulation, 2010; Prockop et al (US PGPub 2017/0145385). The cell culture protocols of Chow et al, Lian et al, and Prockop et al rely on provision of specific growth conditions, including cytokines, density limitations, and optionally formation of embryonic bodies, but notably do not require contacting with exogenous RNA molecules encoding reprogramming factors. As of the effective filing date there was no teaching in the art regarding reprogramming of iPSCs to MSCs using synthetic RNA molecules encoding reprogramming factors.
Thus it is concluded that the specification fails to provide sufficient information to show that Applicants were in possession of a method of reprogramming iPSCs to MSCs using synthetic RNA encoding reprogramming factors. The specification fails to provide any specific reprogramming factors that would achieve reprogramming from iPSCs to MSCs, and this information was not readily known in the prior art. As such, the claims are rejected under 35 USC 112(a) for failing to comply with the written description requirement.
Claims 1, 4-14, 19-21, 35, 37, and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims under rejection are drawn to methods involving an active step of “reprogramming induced pluripotent stem cells (iPSCs) into mesenchymal stem cells (MSCs),” wherein the reprogramming comprises “contacting an iPSC with one or more synthetic RNA molecules encoding a reprogramming factor”. The issue at hand is whether the specification provides sufficient information to enable one of ordinary skill in the art to successfully reprogram an iPSCs into MSCs using one or more synthetic RNA molecules encoding a reprogramming factor without undue experimentation.
Regarding the nature of the invention: In the instant case, the nature of the invention is related to cell reprogramming using non-viral, RNA-based means (See specification at Pg 20, ln 1-5). Cellular reprogramming is a complex science, involving control of gene and protein expression and regulation to achieve manipulation in differentiation status and phenotype of cells. While a complex science, several pathways were well explored and well-known at the time the invention was filed. Specifically, as of the effective filing date, it was known how to reprogram somatic cells to iPSCs using mRNA encoding specific transcription factors Oct4, Sox3, Klf4, c-Myc, 1-Myc, Tert, Nanog and/or Lin 28 (See Warren et al, Cell Stem Cell, 2010; See Angel Thesis, 2011).
Regarding the relative skill of those in the art: The artisan of ordinary skill in this field would be a highly skilled scientist, holding advanced degrees and having extensive background in cellular and molecular biology.
Regarding the state of the prior art: More specific to differentiation of iPSCs to MSCs, the state of the art, as of the effective filing date, did include disclosure of differentiation iPSCs to MSCs using various cell culture protocols (See Chow et al, Stem Cell Research, 2017; Lian et al, Circulation, 2010; Prockop et al (US PGPub 2017/0145385). The cell culture protocols of Chow et al, Lian et al, and Prockop et al rely on provision of specific growth conditions, including cytokines, density limitations, and optionally formation of embryonic bodies, but notably do not require contacting with exogenous RNA molecules encoding reprogramming factors. However, as of the effective filing date there was no teaching in the art regarding reprogramming of iPSCs to MSCs using synthetic RNA molecules encoding reprogramming factors.
Regarding the amount of direction and guidance in the specification: The specification fails to disclose any specific reprogramming factors (that could be encoded via synthetic RNA) that would achieve reprogramming of an iPSC to an MSC. Rather, disclosure of use of reprogramming factors is limited to those capable of reprogramming non-pluripotent cells to iPSCs (see Fig 1; specification at Pg 20, ln 6 through Pg 23, ln 30; see Example 1 at Pg 55). The specific reprogramming factors recited in claim 19 are disclosed as effective to reprogram somatic cells (e.g. fibroblasts) into iPSCs (See, e.g., Pg 20, ln 6-13). The only disclosure of reprogramming iPSCs to MSCs involves subjecting iPSCs to ‘a 21-day high yield monolayer protocol’ (See Pg 23, ln 31-Pg 24, ln 2; Example 1 at Pg 55). The details of this protocol are not provided.
Regarding presence or absence of working examples: The specification provides no working examples where iPSCs are reprogrammed into MSCs by contacting the MSCs with synthetic RNAs encoding reprogramming factors.
Taking into consideration the factors discussed above, it is concluded that one having ordinary skill in the art would not have sufficient information or knowledge, based on the teachings of the specification and available in the prior art, to successfully reprogram iPSCs to MSCs using one or more synthetic RNA molecules encoding reprogramming factors without undue experimentation. Neither the current application nor the state of the art provide any guidance on which reprogramming factors would be effective to reprogram iPSCs to MSCs, thus the artisan of ordinary skill, though highly educated and experienced, would have no starting point on which of the thousands-to-millions of genes or proteins should be manipulated in order to achieve directed cell differentiation from iPSC to MSCs. Placing this experimental burden on the reader would amount to undue experimentation. Therefore the claims are considered to fail to comply with the enablement requirement of 35 USC 112(a).
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 6 and 7 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 claims 6 and 7: The terms “low” and “reduced” (in the context of low or reduced inflammation or low or reduced immunogenicity) in claims 6 and 7 are relative terms which renders the claim indefinite. The terms “low” and “reduced” 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. Specifically, there is no threshold by which to measure “low”, nor “reduce”. Any value can be considered “low or reduced” compared to a higher value. Each term, individually, suffers from this deficiency. The claims are held indefinite.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9, 13 and 14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 9, 13 and 14: Each of claims 9, 13 and 14 attempt to further define the composition of claim 1 by further limiting the MSCs. However, the limitations of “being multipotent” (see claim 9), “expressing one or more of CD73, CD90 and CD105” (claim 13) and “not expressing one or more of CD14, CD34 and CD45” (claim 14) are, in fact, part of the minimum criteria for a cell to be called an MSC. In support, see Dominici et al (Cytotherapy, 2006) at Table 1. Therefore, none of claims 9, 13 or 14 further limit the MSCs of the composition of claim 1, and thus don’t further limit the composition of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim 41 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chow et al (Stem Cell Research, 2017), evidenced by “CytoTune®-iPS Reprogramming Kit” User Guide by Invitrogen b Life Technologies (2014).
Chow et al generate iPSC-derived MSCs for use in therapeutic modulation of inflammatory disorders (See abstract).
Chow et al generate iPSCs by contacting canine fibroblasts with CytoTune iPS Reprogramming kit (See Chow et al, “2.1. Generation of canine induced pluripotent stem cells”). The CytoTune iPS Reprogramming kit contains vectors expressing Oct3/4, Sox2, Klf4, and c-Myc (See CytoTune®-iPS Reprogramming kit user guide at Pg 2). Thus, the iPSCs contained exogenous RNA encoding each of Oct3/4, Sox2, Klf4, and c-Myc.
Chow et al generate iPSC-derived MSCs (iMSCs) by culturing the iPS colonies under specific culture conditions (See Chow et al, “2.2. Generation of iPS-derived mesenchymal stem cells (iMSC)”).
Regarding claim 41: The iMSCs of Chow et al read on the composition of claim 41. Specifically, the iMSCs are MSCs. Due to their derivation from the parent iPSCs, the MSCs contain exogenous synthetic RNA molecules that encode for Oct3/4, Sox2, Klf4, and c-Myc, which read on reprogramming factors.
Chow et al report the iMSCs have greater expression of anti-inflammatory cytokines IL-13, IL-22, and IL-27 compared to BM-MSCs (See Chow et al, Pg. 229). This matches the protein secretion signal required by the claim.
Claim Rejections - 35 USC § 103
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.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Chow et al (Stem Cell Research, 2017).
The teachings of Chow et al are set forth above.
Regarding claim 42: The method of Chow et al produces iMSCs. The iMSCs satisfy the physical/biochemical limitations of the MSCs required by claim 42. The step of producing the iMSCs reads on the (a) obtaining a MSC step of the claim.
Chow et al does not administer the iMSCs to subjects in need of treatment of an inflammatory and/or immunomodulatory disease.
However, Chow et al teaches that the iMSC have potential for treatment of spontaneous inflammatory diseases in pet dogs (See Chow et al, Pg 231, col. 2). Based on this suggestion, it would have been prima facie obvious to have administered an effective amount of the MSCs for therapy to a pet dog having spontaneous inflammatory diseases (patient in need of treatment of an inflammatory disease). One would have had a reasonable expectation of success based on the fact that iMSCs have high gene expression of anti-inflammatory cytokines. This conclusion of obviousness is based on a teaching, suggestion or motivation taught in the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633
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