The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/04/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 12-18 and 28-36) in the reply filed on 12/17/2024 is acknowledged.
Claims 52-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/20/2016.
The Restriction Requirement was previously made Final.
Claim 35 has been canceled. Claims 12-18,28-35 are currently under consideration.
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 12-18,28-35 remain 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 rejection of claim 35 is rendered moot by the cancelation of the claim.
Claim 12 has been clarified with regard to the previous grounds of rejection but the amendments raise new issues. The added “wherein” clause is unclear. There are two parts to the clause and it is not clear if the “and contacting” phrase is an additional method step or is intended to limit the Smad1/5/8 pathway activator to an RARg agonist. It is also unclear if the “does not comprise” modifies “contacting…with an agonist or activator of retinoic acid receptor g” such that the claim excludes an agonist or activator of retinoic acid receptor g. The same issue is present in claims 28 and 30. Claims 12, 28 and 30 are interpreted as limiting the activating Smad1/5/8 signaling pathway by culture in the presence of a RARg agonist.
The grounds of rejection of claim 13 is withdrawn in light of the amendment to the claim.
Claim 28 is unclear in reciting contacting with an agonist of RARg. This is already recited in claim 12 so it is not clear if this is an additional step or a redundancy.
Claim 35 is unclear because it requires contacting cells with an agonist of RARg but this step is already included in parent claims. It is not clear if this is a redundant limitation or if there is an additional active method step being added/limited by the claim.
Claims 13-18,28-35 are also unclear as they depend from claim 12.
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 12-18,28-34 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the claimed method wherein said mesodermal cell or cardiac progenitor cell is simultaneously contacted with an exogenous activator of the Smad1/5/8 signaling pathway and an exogenous inhibitor of the Wnt signaling pathway in the same cell culture medium, thereby activating said Smad1/5/8 signaling pathway and inhibiting said Wnt signaling pathway in said mesodermal cell or cardiac progenitor cell, further wherein the RARg agonist is BMS961 does not enable carrying out the method with any RARg agonist or carrying out the methos wherein the activating and inhibiting occur successively in culture. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). 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. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The inventive nature appears to be the method of activating the Smad1/5/8 pathway to obtain ventricular cardiomyocytes.
The specification provides working examples 2-4 with headings stating, “Inducing differentiation of PSCs into VMs in vitro” and each example referencing Figures 9-11, respectively, for a timeline depicting the addition of factors relevant to each example. Each example ends by stating a large number of beating cardiomyocytes was obtained. The examples do not state that ventricular cardiomyocytes are obtained. The Specification does teach that Figure 15 shows ventricular cardiomyocytes (VMs) are obtained from working example 2 and Figure 17 supports obtaining VMs from the conditions of working example 3.
Working Example 2 conditions were as follows:
During the first 3 days of differentiation, the differentiation medium contained activin A (10 ng/mL), BMP4 (6 ng/mL), and bFGF (6 ng/mL). At the end of day 3, the medium was exchanged with a BMP2/4 inhibitor, noggin (300 ng/mL) added to the medium. At the end of day 5, the medium was replaced with vitamin A-free, B27 supplemented RPMI1640 medium. A Wnt3a inhibitor, DKK1 (300 ng/ml.) and BMP4 (10 ng/ml) were also added to the medium. At the end of day 8, the medium was replaced with medium containing 300 ng/mL DKKI1 only. At the end of day 10, the medium was replaced with growth factor-free medium.
Working Example 3 conditions were as follows:
At the end of day 3, the medium was exchanged with differentiation medium containing a BMP2/4 inhibitor, noggin (300 ng/mL). At the end of day 5, the medium was replaced with vitamin A-free, B27-containing RPMI 1640 medium containing a Wnt3a inhibitor, DKK1 (300 ng/mL), and RARg activator, BMS961 (0.1 uM, Tocris). At the end of day 8, the medium was replaced with medium containing 300 ng/mL DKK1 only. At the end of day 10, the medium was replaced with growth factor-free medium.
Working Example 4 conditions were as follows:
At the end of day 3, the medium was exchanged with differentiation medium containing a BMP2/4 inhibitor, noggin (300 ng/mL). At the end of day 5, the medium was replaced with vitamin A-free, B27-containing RPMI1640 medium containing a Wnt3a inhibitor, DKK1 (300 ng/mL), as well as antagonists of RARa and RARb, BMS195614 (0.1 uM) and LE135 (0.5 uM), respectively. At the end of day 8, the medium was replaced with medium containing 300 ng/mL DKKI1 only. At the end of day 10, the culture medium was replaced with growth factor-free medium.
The italicized conditions are understood to be the conditions that direct differentiating mesodermal cells into ventricular cardiomyocytes. Lee (2017, Cell Stem Cell, 21:179-194) teaches that atrial and ventricular cardiomyocytes derive from different mesodermal populations. Lee found that altering differentiation conditions can skew differentiation into populations that form either atrial or ventricular cardiomyocytes (see page 183, left column). Applicant has clarified that BMP4 or agonists of RARg or antagonists if RARa/b drives cardiomyocytes along the ventricular fate path as opposed to the atrial path, and Wnt inhibition drives cardiac differentiation. The claims do not recite any order of steps and encompass applying conditions to specify a ventricular fate prior to directing cells to become cardiomyocytes.
With regard to the RAR-g agonist, the specification teaches use of BMS961. The working examples also teach culture with BMS195614 as a RARa/b antagonist, or with BMP, which activates SMAD signaling. The Specification also teaches culture with BMS961, a RARg activator. Powala (Int. J. Mol. Sci. 2024, 25, 6568. https://doi.org/10.3390/ijms2512656) taught that the RARg agonist palovarotene inhibits Smad 1/5/8 signaling (Section 6.3). RAR binding selectivities and signaling is highly complex. Thus, SMAD signaling can be activates with the RARa/b antagonist BMS614 and with the RARg agonist BMS961 but SMAD signaling is inhibited with the RARg agonist palovarotene. The specification fails to teach the characteristics of a RARg agonist that will have the property of activating Smad signaling in the manner of BMS961 such that one of skill in the art could predictably use any RARg agonist and obtain similar results, and at least 80% ventricular as claimed.
Applicant traverses the rejection and amends claim 12 to limit the mode of activating the Smad1/5/8 signaling pathway. The rejection has been amended to take into account Applicant’s comments and amendments. As set forth above, Lee teaches that atrial and ventricular cardiomyocytes derive from different mesodermal populations. Lee found that altering differentiation conditions can skew differentiation into populations that form either atrial or ventricular cardiomyocytes (see page 183, left column). Lee also teaches that various ratios of BMP and Activin in pluripotent stem cell differentiation can lead to differentiation away from the cardiomyocyte path, or towards atrial vs ventricular differentiation. Thus, conditions used to differentiate pluripotent stem cells into mesodermal cells are important in order to obtain cells capable of cardiomyocyte fates as well as ventricular cardiomyocytes.
Applicant argues that claim 12 is drawn to a particular way for promoting pluripotent stem cell differentiation into ventricular cardiomyocytes. This argument is not persuasiove as the claim only recites some broad method steps for differentiating mesoderm or cardiac progenitor cells into ventricular cardiomyocytes.
It is noted that while Lee supports that mesodermal cells that are moving towards the ventricular lineage can become atrial, the opposite is not shown and claim 12 requires the population comprise 80% ventricular cardiomyocytes.
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 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.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
The rejection of claim(s) 12-18,28-29 and 34-36 under pre-AIA 35 U.S.C. 102(b) (and alternatively 102(e), see below) as being anticipated by WO2011157029 (Ma, filed 11/11/2010; published 12/22/2011) is withdrawn.
This rejection is withdrawn as Ma taught use of BMS195614, which is not a RARg agonist and the claims are interpreted as requiring such. The wherein claunse of amended claim 12 is read as, “…wherein the Smad1/5/8 pathway is activated by contacting the mesodermal cell or cardiac progenitor cell with an agonist or activator of retinoic acid receptor g.”
The rejection of claim(s) 12-18,28-29 and 34 rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Zhang (2010, Cell Research volume 21, pages579–587) is withdrawn as Zhang taught use of BMS195614, which is not a RARg agonist and the claims are interpreted as requiring such. The wherein claunse of amended claim 12 is read as, “…wherein the Smad1/5/8 pathway is activated by contacting the mesodermal cell or cardiac progenitor cell with an agonist or activator of retinoic acid receptor g.”
The rejection of claims 12-18 and 28-29 are rejected under pre-AIA 35 U.S.C. 102(e) as being anticipated by Palecek et al (US 20130189785) is withdrawn in light of the incorporation of the limitations of claim 30 into claim 12.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
The rejection of claims 12-18,28-29,34-36 on the ground of nonstatutory double patenting as being unpatentable over claims 5-7,15 and 18 of U.S. Patent No. 9,273,286 is withdrawn.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached on M-F 6AM-2:30PM.
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/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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