DETAILED ACTION
This action is in reply to papers filed 7/31/2023. Claims 1-3 and 5-14 are pending and examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230374460A1, Published 11/23/2023.
Maintained Rejection(s)
The 35 U.S.C. 101 rejection of claims 1-13 is maintained. Applicant’s arguments will be addressed following maintained rejection.
Withdrawn Rejection(s)
The 35 U.S.C. 102(a)(1)/(a)(2) rejection of claims 1-2, 4-6 and 9-11 as being anticipated by Palecek et al. (PgPub US20130189785A1, Published 7/25/2013, Filed 10/12/2012) as evidenced by Yu et al. (Science. 2007 Dec 21;318(5858):1917-20.) is withdrawn in view of amendments made to independent claim 1.
The 35 U.S.C. 102(a)(1)/(a)(2) rejection of claims 1-2, 4, 6-7 and 9-12 as being anticipated by Wu et al. (PgPub US 20140134733A1, Published 7/13/2015, Filed 11/13/2013) as evidenced by Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.) is withdrawn in view of amendments made to independent claim 1.
The 35 U.S.C. 103 rejection of claims 3, 5 and 13 as being unpatentable over Wu et al. (PgPub US 20140134733A1, Published 7/13/2015, Filed 11/13/2013) and Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.) as applied to claims 1-2, 4, 6-7 and 9-12 above, and further in view of Yamanka et al. (PgPub US20160122716A1, Filed 5/9/2014) is withdrawn in view of amendments made to independent claim 1. .
The 35 U.S.C. 103 rejection of claim 8 as being unpatentable over Wu et al. (PgPub US 20140134733A1, Published 7/13/2015, Filed 11/13/2013) and Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.) as applied to claims 1-2, 4, 6-7 and 9-12 above, and further in view of Yazawa et al. (J Cardiovasc Transl Res. 2013 Jan 9;6(1):1–9) is withdrawn in view of amendments made to independent claim 1.
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 1-3, 5-13 remain and new claim 14 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. Although maintained, the rejection has been updated to reflect amendments to independent claim 1.
The claim(s) recite a composition comprising cardiac differentiated stem cells, wherein the cardiac differentiated stem cells are differentiated from induced pluripotent stem cells cultured in a monolayer in the presence of one or more glycogen synthase kinase 3 (GSK3) signaling inhibitors and/or one or more WNT signaling inhibitors, wherein the induced pluripotent stem cells are derived from cells transfected with episomal vectors in complex with liposomes, wherein the cardiac differentiated stem cells do not have viral integration in their
genome and the pluripotent stem cells do not have viral integration in their genomes. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following:
Independent claim 1 is drawn to a composition comprising cardiac differentiated stem cells, wherein the cardiac differentiated stem cells are differentiated from induced pluripotent stem cells in the presence of one or more glycogen synthase kinase 3 (GSK3) signaling inhibitors and/or one or more WNT signaling inhibitors, wherein the iPS cells are derived from cells transfected with episomal vectors in complex with liposome. Additionally, the claim requires the cardiac differentiated stem cells to not have viral integration in their genomes. In addition, the claims require the pluripotent stem cells to also not have viral integration.
Claim interpretation: The recitation “wherein the cardiac differentiated stem cells are differentiated from induced pluripotent stem cells cultured in a monolayer in the presence of one or more glycogen synthase kinase 3 (GSK3) signaling inhibitors and/or one or more WNT signaling inhibitors, wherein the induced pluripotent stem cells are derived from cells transfected with episomal vectors in complex with liposomes, wherein the cardiac differentiated stem cells do not have viral integration in their genome and the pluripotent stem cells do not have viral integration in their genome ” is being interpreted as a product-by-process limitation. That is, the product - cardiac differentiated stem cells- are produced by the process of differentiating induced pluripotent stem cells in a monolayer in the presence of one or more glycogen synthase kinase 3 (GSK3) signaling inhibitors and/or one or more WNT signaling inhibitors. A product-by-process claim is not limited to manipulations of the recited steps, but instead is only limited to the structure implied by the steps. See MPEP 2113.
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category. See MPEP 2106.03. Here, the claim recites a composition of cardiac differentiated stem cells. Because cardiac differentiated stem cells are a composition of matter, the claims falls within a statutory category. (Step 1: YES)
Step 2A, Prong One: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. As explained in MPEP 2106.04(II) and the October 2019 Update, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim. Because claim 1 recites a nature-based product limitation (cells), the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception. MPEP 2106.04(c)(I). MPEP 2106.04(c)(I)(A). The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. MPEP 2106.04(c)(II).
Here, the closest natural counterpart to the cardiac differentiated stem cells of claim 1 are naturally occurring cardiac stem cells. The art, as exemplified in previously cited Bearzi et al. (Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14068-73), teaches the human heart contains clusters of human Cardiac Stem Cells (hCSCs) that are intimately connected by gap junctions and adherens junctions to myocytes and fibroblasts (Fig. 1 A–C). Bearzi teaches these human c-kit-positive cardiac cells possess the fundamental properties of stem cells: they are self-renewing, clonogenic, and multipotent. Furthermore, hCSCs differentiate predominantly into cardiomyocytes and, to a lesser extent, into smooth muscle cells and endothelial cells (Abstract). Accordingly, the claim recites a judicial exception, and the analysis must therefore proceed to Step 2A Prong Two.
Step 2A Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. 2019 PEG Section III(A)(2), 84 Fed. Reg. at 54-55. And while claim 1 recites a process by which the cardiac differentiated stem cells are produced by, the Courts have consistently held that a product-by-process claim is not limited to manipulations of the recited steps, but instead is only limited to the structure implied by the steps. As such, the claim does not recite any additional elements besides the judicial exception. (Step 2A: YES)
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. As discussed with respect to Step 2A Prong Two, the claim fails to include anything more than the judicial exception. (Step 2B: NO). The claim is not eligible.
Applicant’s Arguments/Response to Arguments
Applicant argues: In conjunction with the USPTO Eligibility Guidance, the USPTO has released a set of explanatory examples relating to nature-based products. On page 14 of the USPTO "Nature Based Products" examples issued in December 2014, claim 2 reads:
"2. An isolated man-made human pacemaker cell expressing marker Z."
USPTO examples relating to nature-based products, page 14.
This claim 2 is considered patent-eligible: "The claim is limited to human pacemaker cells that express marker Z, which are nature-based products. No human pacemaker cells expressing marker Z are naturally occurring. As described in the specification, the claimed cells are exact
genetic replicas of naturally occurring pacemaker cells, that were produced from naturally occurring stem cells. However, the claimed cells are phenotypically different than natural pacemaker cells, in that they express marker Z and have increased oxygen utilization efficiency. Further, these phenotypic differences were created by applicant's efforts (e.g., by culturing the stem cells in a particular growth medium in the presence of growth factor A, at various
temperatures), and were not the work of nature. These phenotypic differences
rise to the level of a marked difference, and accordingly the claimed cell is not a
"product of nature" exception. Thus, the claim is not directed to an exception
(Step 2A: NO), and qualifies as eligible subject matter." USPTO examples relating to nature-based products, page 14. Emphasis added.
Applicant’s arguments: Applicant’s arguments have been fully considered, but are not found persuasive. This is because the fact pattern of the 2014 USPTO example is distinct from that of instant claims. Critically, the 2014 Example notes that the phenotypic differences were expression of marker Z and an increased oxygen utilization efficiency. These differences were derived from Applicant’s hand and not the work of nature. No such phenotypic differences can be readily discerned from the instant invention’s cardiac differentiated stem cells.
While the iPS cells are structurally different- insofar that they are produced via episomal transfection in complex with liposomes, the derived cells- the cardiac differentiated stem cells are not structurally different. As claimed, the cardiac differentiated stem cells do not have viral integration in their genome. Stated another way, if one were to place the cardiac differentiated stem cells of the instant claims and naturally occurring cardiac differentiated stem cells next to each other- absent evidence to the contrary- there would be no phenotypical difference. This is unlike the 2014 USPTO example as the cells therein expressed a marker and had an increased oxygen utilization efficiency when compared to their naturally occurring counterpart.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
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.
Prior Art Rejection 1
Claims 1-2, 6-7, 9-12 and 14 as being unpatentable over Wu et al. (PgPub US 20140134733A1, Published 7/13/2015, Filed 11/13/2013; previously cited), Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.; previously cited) and Lavitrano et al. (PgPub US20090158450A1, Published 6/18/2009).
Wu et al. teach methods for producing a cardiomyocyte population from a mammalian pluripotent stem cell population. Wu teaches aspects of the methods include using a Wnt signaling agonist and antagonist, each in minimal media, to modulate Wnt signaling (Abstract). Specifically, and with regards to claim 1 (in-part), Wu teaches a method of producing a cardiomyocyte population from a human induced pluripotent stem cell (iPSc) population cultured in a monolayer (Pg. 10,para. 85), the method comprising: (a) contacting the mammalian pluripotent stem cell population with an effective amount of an inhibitor of GSK-3β, such as BIO or CHIR-99021 (as in claim 2) (Pg. 1, para. 8), in a minimal media for a period of about 12-60 hours, to produce an agonist-contacted cell population; and (b) contacting the GSK-3β inhibited cell population with an effective amount of a Wnt signaling antagonist in a minimal media for a period of at least 12 hours (Pg. 1, para. 7). Wu teaches using the 59FSDNC3 and 64FSDNC1 hiPSC cell lines (Pg. 2, para. 18). As evidenced by Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.), the 59FSDNC3 hiPSC cell line was derived from skin fibroblasts (as in claim 6) from a breast cancer patient (as in claim 7) (see Pgs. 8-9 of Burridge). Wu teaches CHIR-99021 can be used at 4-15 μM (as in claim 9, claim 10 and claim 11) and BIO can be used at 2-5 μM (as in claim 12) (Pg. 18, para. 175). Wu teaches the induced pluripotent stem cells are derived from cells transfected with episomal plasmids (OCT4, SOX2, KLF4, L-MYC, LIN28, short hairpin p53) (as further in claim 1 and as in claim 14) (Pg. 2, para. 18). Insofar as episomal vectors do not integrate in the genome of a cell, said cardiac differentiated stem cells do not have viral integration in their genome and said pluripotent stem cells do not have viral integration in their genome.
Wu notes that deriving hiPSCs from patients with specific cardiac diseases, differentiating them to cardiomyocytes using the subject methods, and then performing electrophysiological and molecular analyses will provide a powerful tool for deciphering the molecular mechanisms of disease. Continuing, Wu adds that the combination of novel drug discovery and efficacy testing with cardiomyocytes derived from patient-specific hiPSCs is a potentially groundbreaking option for personalized medicine (Pg. 15-16, para. 135).
However, Wu et al. fails to teach the episomal vectors are in complex with liposomes (as further in claim 1).
Before the effective filing date of the claimed invention, Lavitrano et al. taught methods method for the transfer of DNA sequences or exogenous genes into animal cells by means of the use of episomal vectors (Abstract). Lavitrano teaches that in accordance with a particularly preferred embodiment of the invention, the episomal vectors may be included inside carriers, for example pharmaceutical type carriers such as liposomes, so as to further increase the level of transfection thanks to the barrier protecting against DNAse action (Pg. 3, para. 46).
When taken with the teachings of Wu et al., wherein Wu teaches methods for producing a cardiomyocyte population from a human induced pluripotent stem cell population, wherein said method comprises transfecting cells with an episomal vector comprising reprogramming factors, on of ordinary skill in the art would have found it prima facie obvious to complex the episomal vector with liposomes because Lavitrano teaches an advantage of liposomes is that they increase the level of transfection thanks to the barrier protecting against DNAse action.
Thus, the combination would have been prima facie obvious.
Prior Art Rejection 2
Claim(s) 3, 5 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (PgPub US 20140134733A1, Published 7/13/2015, Filed 11/13/2013; previously cited), Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.; previously cited) and Lavitrano et al. (PgPub US20090158450A1, Published 6/18/2009) as applied to claims 1-2, 6-7, 9-12 and 14 above, and further in view of Yamanaka et al. (PgPub US20160122716A1, Filed 5/9/2014; previously cited).
The teachings of Wu et al., Burridge et al. and Lavitrano et al. are relied upon as detailed above. And although Wu teaches contacting the GSK-3β inhibited cell population with an effective amount of a Wnt signaling antagonist, Wu fails to teach the Wnt signaling antagonist is IWP-3 (as in claim 3).
Before the effective filing date of the claimed invention, Yamanaka et al. teach a method for efficiently producing cardiomyocytes from pluripotent stem cells (Abstract). Yamanka teaches the pluripotent stem cells are induced pluripotent stem cells derived from fibroblasts of a healthy patient (as in claim 5) (Pg. 5, para. 55). Yamanaka teaches the method, as a last step (Pg. 1, para. 11-15), contacts the pluripotent stem cells with the Wnt inhibitor, IWP-3, at a concentration of 2 μM (as in claim 3 and claim 13) (Pg. 6, para. 70).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (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."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Wu et al., Burridge et al. and Lavitrano et al., wherein the combination teaches methods for producing a cardiomyocyte population from episomal-liposome complex derived human induced pluripotent stem cell population, wherein said method comprises contacting the episomal-liposome complex derived human induced pluripotent stem cell with a GSK-3β inhibitor and an effective amount of a Wnt signaling antagonist with the teachings of Yamanaka et al., wherein Yamanaka teaches contacting human pluripotent stem cells with the Wnt signaling antagonist IWP3 as a final step in differentiating pluripotent stem cells into cardiac differentiated stem cells. That is, the skilled artisan would have found it prima facie obvious use the IWP3 of Yamanka as the Wnt signaling antagonist of Wu because Yamanka evidences the suitability of the use of IWP3 as a Wnt signaling antagonist in producing a cardiomyocyte population from a human induced pluripotent stem cell population.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 3
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (PgPub US 20140134733A1, Published 7/13/2015, Filed 11/13/2013; previously cited), Burridge et al. (Nat Med. 2016 Apr 18;22(5):547–556.; previously cited) and Lavitrano et al. (PgPub US20090158450A1, Published 6/18/2009) as applied to claims 1-2, 6-7, 9-12 and 14 above, and further in view of Yazawa et al. (J Cardiovasc Transl Res. 2013 Jan 9;6(1):1–9; previously cited).
The teachings of Wu et al., Burridge et al. and Lavitrano et al. are relied upon as detailed above. And although Wu teaches deriving hiPSCs from patients with specific cardiac diseases, differentiating them to cardiomyocytes using the subject methods, and then performing electrophysiological and molecular analyses will provide a powerful tool for deciphering the molecular mechanisms of disease (Pg. 15, para. 135), Wu fails to teach the iPS cells are derived from Timothy’s Syndrome patients (as in claim 8).
Before the effective filing date of the claimed invention, Yazawa teaches Timothy syndrome (TS) is a multisystem disorder caused by gain-of-function mutations in the L-type calcium channel CACNA1C gene. Yazawa teaches mouse models of TS do not fully recapitulate the human disorder and, in particular, lack the postnatal lethality that occurs in patients with TS. Yazawa teaches this is likely because mouse cardiomyocytes have different electrical properties from their human counterparts. In order to investigate human-specific disease mechanisms of TS, Yazawa and colleagues generated human cardiomyocytes from TS patients using induced pluripotent stem cell (iPSC) technology (as in claim 8), examined cellular phenotypes in contraction, electrical signal and calcium handling, and performed drug tests to find lead compounds for TS (Abstract; paragraph bridging PG. 2 and Pg. 3).
When taken with the teachings of Yazawa et al., wherein Yazawa teaches iPS cells derived from Timothy’s syndrome patients, one of ordinary skill in the art would have found it prima facie obvious to substitute the patient derived iPS cells of Wu et al. for the iPS cells of Yazawa et al. because Wu contemplated deriving hiPSCs from patients with specific cardiac diseases, differentiating them to cardiomyocytes using the subject methods, and then performing electrophysiological and molecular analyses. That is, the skilled artisan would have found it prima facie obvious to derive iPS cells from Timothy’s syndrome patients using the method of Wu et al. in order to decipher the molecular mechanisms of the disease. A reasonable expectation of success is present as Yazawa achieved success in deriving iPS cells from Timothy’s syndrome patients.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
