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 .
Election/Restrictions
Applicant’s election of Group I and the species of: CRISPR/Cas systems; reduced expression by insertion or deletion of nucleic acid sequence at a locus encoding HCN4, CAVNA1H and SLC8A1; and a stem cell line, the reply filed on 13 July 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-2, 15, 20, 22, 25, 36, 40, 43, 46, 53, 55, 58, and 139 and read on the elected species.
Claims 72, 122, 210, 231-233 are withdrawn. It should be noted that while Applicant asserted claim 210 reads upon the elected species, it depends from Claim 72 which is directed to the withdrawn invention of a pluripotent stem cell. Thus, it is withdrawn from examination.
Claim Objections
Claim 1 is objected to because of the following informalities: The claim recites abbreviations that are not spelled out in their first appearance. Appropriate correction is required.
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 1-2, 15, 20, 22, 25, 36, 40, 43, 46, 53, 55, 58, and 139 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.
Claim 1 is primarily indefinite because it recites a product and process in the same claim. MPEP 2173.05(p)(II) discusses how a single claim which claims both a product and the method steps of using the product is indefinite under 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303 (Fed. Cir. 2011). In Katz, a claim directed to “A system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data” was determined to be indefinite because the italicized claim limitation is not directed to the system product itself, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. The case law applies to the instant claim(s) which recite a product (a cardiomyocyte) but modifies the cell by stating “HCN4, CACNA1H, and SLC8A1 activities are at least partially inhibited, and KCNJ2 activity is at least partially stimulated” in said cell. It is unclear, when direct infringement of the claim occurs: upon producing an in vitro-differentiated human cardiomyocyte or upon assessing that the activities of certain genes are inhibited or stimulated. This is rendered further indefinite depending claims that recite wherein inhibition/stimulation is altered “by at least 10% or 1-fold” (claim 20); and claim 22 recites, “wherein the genetic manipulation method is…”. This affects the scope of all depending claims.
Additionally, the term “at least partially inhibited” and “at least partially stimulated” in claim 1 are relative term which render the claim indefinite. The term “partially inhibited” and “partially stimulated” are neither defined by the claim, nor does the specification provide a standard for ascertaining the requisite degrees that constitute partial inhibition or stimulation. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. This also affects the scope of all depending claims.
The term “reduced” in claims 2, 25 and 139 is a relative term which renders the claims indefinite. The term “reduced” is neither defined by the claim, nor does the specification 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. Without a standard it is unclear what reduced means in the context of the invention.
The term “increased” in claim 139 is a relative term which renders the claim indefinite. The term “increased” 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. Absent a standard it is unclear what the scope of increased means in the context of the invention.
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 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a nature-based product without significantly more. The claim(s) recite(s) an in vitro-differentiated human cardiomyocyte in which HCN4, CACNA1H, and SLC8A1 activities are at least partially inhibited, and KCNJ2 activity is at least partially stimulated. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim fails to differentiate from human cardiomyocytes that occur in nature.
The following art discloses cardiac ventricular myocytes have altered gene expression in early onset diabetes relative to control (Salem et al., Exp Physiol. 97(12): 1281-1291, 2012). Specifically, the art teaches HCN4, CACNA1H, SLC8A1 and KCNJ2 are all altered compared to control or over time as diabetes develops. While the prior art is concerned with gene expression, and not activity – as claimed – the prior art teaches how something like elevated fasting blood glucose can alter cardiac gene ion channel expression. Furthermore, the art prior to filing teaches that the activities of each of these ion channels can be inhibited or stimulated through altering ion concentration, or by pharmaceutical agonists/antagonists. For example, HCN4 is the Hyperpolarization-activated cyclic nucleotide-gated K+ channel 4, which underlies the Pacemaker current (a.k.a. the funny current If), and its activity can be altered by in vitro patch-clamp control of whole cell conductance, by altering K+ ion levels, by altering cyclic nucleotide levels, or through application of any of the known HCN4 current inhibitors such as Ivabradine, ZD7288, Zatebradine or Carvedilol. Similarly, CACNA1H can be decreased in vitro by applying ABT-639, Ethosuximide, Pimozide or Pentamidine; and SLC8A1 currents can be inhibited by the presence of its selective inhibitor, CB-DMB. While KCNJ2 activity can be augmented or stimulated by contacting the cardiomyocyte comprising this channel with Zacopride. (See attached Google search strategies for all of these pharmacological agents). Thus, the in vitro-differentiated human cardiomyocyte in which HCN4, CACNA1H, and SLC8A1 activities are at least partially inhibited, and KCNJ2 activity is at least partially stimulated, does not differentiate over a naturally-occurring human differentiated cardiomyocyte that has been contacted in vitro with a cocktail of Ivabradine, Pentamidine, CB-DMB and Zacopride. This is consistent with the specification (see paragraph [00838]).
For this reason the claim is rejected as being drawn to a nature-based product without significantly more.
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 53, 55 and 58 are 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 in vitro human cardiomyocyte derived from a pluripotent stem cell, iPSC, patient-derived stem cell or stem cell line; does not reasonably provide enablement for human cardiomyocytes derived from any other “starting material”. 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 the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The specification teaches stem cells serve as the starting material for producing human cardiomyocytes (paragraph [0003]) and these stem cells are derived from a PSC or ESC (paragraphs [0020] and [0090]). There is no other starting material disclosed, therefore, what is enabled by the working examples is narrow in comparison to the breadth of the claims.
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001, (CAFC 1997), the court held that:
"[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art", "[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement".
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. A person having ordinary skill in the art would have to discover starting materials from which the human cardiomyocytes could be derived, in order to demonstrate use of the method with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation. Therefore, Claims 53, 55 and 58 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Allowable Subject Matter
While no claim is allowed at this time, it should be noted that there is no prior art that teaches or suggest the claimed cardiomyocyte that is genetically engineered for: (1) reduced expression of HCN4, CACNA1H, and SLC8A1, relative to non-genetically modified human cardiomyocytes derived from pluripotent stem cells, and (2) expression of a transgene encoding KCNJ2 that is controlled by an endogenous HCN4 regulatory sequence. As allowable subject matter has been indicated, applicant's reply must either comply with all formal requirements or specifically traverse each requirement not complied with. See 37 CFR 1.111(b) and MPEP § 707.07(a).
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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