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 .
Claim Status
Claims 1-15 are currently pending in this application.
Warning: duplicative claims
Applicant is advised that should claim 1 be found allowable, claim 15 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
As the method of claim 1 requires the result of primate pluripotent stem cells becoming ovarian somatic cell-like cells (being obtained in step (3)), the act of inducing differentiation of primate pluripotent stem cells into ovarian somatic cell-like cells implicitly and inherently occurs by performance of claim 1. Therefore, claim 15 is objected to for being substantially duplicative despite differences in wording.
Claim Interpretation
In the claims, the notations “(1-1) culturing,” “(1-2) culturing” “(3-1) culturing” or “(3-2) culturing” are interpreted to denote a sub-step according to the first numeral of a step of claim 1. Note, the order of performing process steps is not ordinarily construed to be any specific order unless specified by the claim or when the claim language, as a matter of logic or grammar, requires that the steps be performed in the order written, or the specification directly or implicitly requires an order of steps. In the instant case, claim 1 clearly requires step (1) occurs before step (2), and step (2) occurs before step (3). Thus, claim 6 requires performing steps (1-1) and (1-2) in that order before step (2). In claim 12, performing the recited steps merely narrows and accomplishes step (3) of claim 1.
Claim Rejections - 35 USC § 112(a), Written Description
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 1-15 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
When the claim is analyzed in light of the specification, the instant invention is directed to methods of culturing primate pluripotent stem cells in a series of steps comprising different antagonists (inhibitors) and agonists to convert them into ovarian somatic cell-like cells.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”
Culturing duration and minimum agent concentration
In the instant case, the claims are broad in that each culturing step encompasses any duration and conditions. The claims are also broad in that the signaling antagonists and agonists may be at any concentration. For example, GSK3 and ROCK inhibitors typically don’t provide inhibitory activity below nanomolar concentrations, e.g., picomolar, MEK inhibitors typically need to be at a concentration over 100 picomolar, and retinoic acid doesn’t provide agonist activity at less than 1 nM. BMP4 typically has no effect on cells at concentrations under 1 ng/mL.
While the specification describes culturing steps lasting at least one day, with optimized embodiments of claim 1 selecting durations of step 1 for 4 days, step 2 for 3 days, and step 3 for a “long-term” starting at day 7, such as for a total method duration of 13-86 days (FIG. 3A-8A, 10A, 14A-15A, 18A, 20A, 20G, 22-23, 32A-60A; Table 6), e.g., with days per steps 1-2-3 patterns of: 2-2-10, 2-2-12, 2-3-11, 3-2-11, 3-3-10, 4-2-10, or 4-3-9.
The application lacks sufficient disclosure as to produce the recited result if step 1 is less than 1 day, step 2 lasts less than 2 days and step 3, and if the toral duration is less than 13 days (FIG. 33B-52B, based on expression of FOXL2 or SF1 (NR5A1)). Furthermore, the application lacks sufficient disclosure as to produce the recited result if the concentration of GSK3 and ROCK inhibitors is below 1 nanomolar, the BMP4 is below, 1 ng/mL, and the MEK inhibitor is below 100 pM.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a method to predictably produce ovarian somatic cell-like cells (e.g., FOXL2+ and/or SF1+) over the scope the claims regarding no minimum durations for each step and no minimum concentrations for many of the agents. Adequate written description requires more than a mere statement of an intended result of practicing the invention and reference to the broadly claimed method described only at a high level of generality.
Medium
The claims are also broad in that the term “medium” encompasses a diverse genus of medium species (see e.g., instant [0032] at pg. 28; to pg. 30, [0037]; Table 2). A “medium” encompass various mammalian cell culture media, vertebrae cell culture media, eukaryotic cell culture media (e.g., for fungi or algae), and prokaryotic cell culture media (e.g., for bacteria and phage).
The representative species described in the specification are all mammalian cell culture media and not representative of the full genus nor indicative of any shared characteristic or component(s) providing a nexus among the encompassed species of media for use in the claimed methods. The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a method of predictably producing ovarian somatic cell-like cells using any medium.
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of a method presently recited in claims 1-15.
35 USC § 112(a), Scope of Enablement
Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to perform the claimed methods over their entire claim scope. However the specification in view of the prior art does enable these methods wherein step (1) is performed for at least 1 day, step (2) is performed for at least 2 days, step (3) is performed for at least 9 days, the GSK3 is at a concentration of at least 1 nM, the ROCK inhibitor is at a concentration of at least 1 nM, BMP4 is at a concentration of at least 1 ng/mL, and the MEK inhibitor is at a concentration of at least 1 pM.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "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 104). 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 weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(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.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of the claims:
Claim 1 is broadly directed to methods of obtaining ovarian somatic cell-like cells by a 3 step method comprising (1) culturing primate pluripotent stem cells in a medium comprising a GSK3 and ROCK inhibitor, (2) culturing the cells resulting from step (1) in a medium comprising a BMP4, retinoic acid, and MEK inhibitor, and then culturing the cells resulting from step 2 in a medium such that at least some of the cells are converted in ovarian somatic cell-like cells.
It is noted that the claims encompass any duration of culturing for each of steps (1)-(3) and the claims encompass any amount of the GSK3, ROCK inhibitor, BMP4, retinoic acid, and MEK inhibitor.
The state of the art:
The prior art teaches methods of making ovarian somatic cell-like cells (e.g., follicular granulosa or theca like cells) from human pluripotent stem cells by culturing in media comprising various agents over many days, such as adherent to a surface or within embryoid bodies (Lan et al., J Clin Endocrinol Metab. 98: 3713-23 (2013), IDS ref.; Jung et al., Nat Commun. 8: 15680 (2017); Yamashiro et al., Science 362: 356-60 (2018)). However, the prior art is silent as to any method comprising the ordered steps recited in claim 1. Thus, these aspects must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such an artisan.
The amount of direction and guidance and working examples provided by Applicant:
Nowhere does the instant specification provide any working embodiment of a method producing ovarian somatic cell-like cells in less than 13 days or with the combinations or recited medium components wherein the GSK3 inhibitor is at a concentration of less than 3 µM and the ROCK inhibitor is at a concentration of less than 10 µM or wherein the BMP4 is at a concentration less than 1 ng/mL and the MEK inhibitor is at a concentration less than 0.3 µM (Example 1-2; FIG. 3-60). Instead, the empirical data in the instant application shows only wherein step 1 lasts at least 1 day, step 2 lasts at least 2 days and the remainder of the method including step 3 is at least 11 days, for a toral duration of 14 days (FIG. 33B-52B, based on expression of FOXL2 or SF1 (NR5A1)). Although the specification provides guidance as to alternative GSK3 inhibitors, ROCK inhibitors, and MEK inhibitors known in the prior art and to the skilled artisan to have similar effects at different concentration ranges; the method relies on a minimal effect occurring inside at least some the culturing cells to produce the requisite result.
Thus, there is no evidence in the instant application or the prior art that the scope of any culturing durations or any concentrations of the agents would predictably produce ovarian somatic cells or the like. Although claims 2-4 set a culturing duration for one step at a time, none of these claims are enabled as all 3 steps require a minimum duration in light of the instant application. Undue and unreasonable experimentation would be required to determine how to shorten the culturing steps, e.g., to less than one hour, and achieve the requisite result, which may never be achievable.
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains, or with which it is most nearly connected, to produce ovarian somatic cell-like cells from primate pluripotent stem cells over the scope of any culturing durations and using the recited agents without any limitations as to their concentrations. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims, undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the desired effect over the full scope of the claims.
Claim Rejections - 35 USC § 112(b)
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 1-15 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 pre-AIA the applicant regards as the invention.
Claims 1 and 12 each recites the term “base medium”, which is not defined in the claims, the instant application or the prior art and thus, a person of ordinary skill in the art would not understand the metes and bounds of the entire genus of base media. In view of instant [0032] (pg. 28), a base medium encompasses an αMEM, neurobasal, neuroprogenitor basal, NS-A, BME, BGJb medium, CMRL 1066, MEM, Eagle MEM, DMEM, GMEM, an Improved MEM Zinc Option, IMDM, Medium 199, DMEM/F12, StemPro-34SFM, Ham's, RPMI 1640, HTF, Fischer's medium, and a mixed medium thereof; but from these embodiments it is unclear what are the necessary shared ingredients/features unifying this group. Furthermore, the instant Examples provide several embodiments of “base” media used in steps 1, 2, or 3 comprising additional components (Examples 1-2). A base medium may or may not include additives such as BMP4, FGF signaling activator, and MEK inhibitor (instant [0064] at pg. 37). If the applicant acts as her own lexicographer to define a term of a claim, the written description must clearly define the claim term and set forth the definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). Claims 2-11 and 13-15 are included in this rejection for depending from indefinite claim 1.
Claims 1 and 15 each recites the relative term “like” with regard to a type of cell or genus of cells named “ovarian somatic cell-like cells.” The current claims, the instant specification, and the prior art all fail to definitively define the term “ovarian somatic cell-like.” “When a term of degree is used in the claim, the examiner should determine whether the specification provides some standard for measuring that degree” and if the specification does not provide some standard for measuring that degree, “a determination must be made as to whether one of ordinary skill in the art could nevertheless ascertain the scope of the claim (e.g., a standard that is recognized in the art for measuring the meaning of the term of degree). See MPEP 2173.05(b) (I). As “like” can mean a variety of deviations from an actual ovarian somatic cell, a person of ordinary skill in the art would not be appraised of the metes and bounds of the scope of the claim with regard to this term as it is not clear what degree of similarity to a bona fide ovarian somatic cell is required. Claims 2-14 are included in this rejection for depending from indefinite claim 1.
Claim 7 recites the term “plane culture,” which is not defined in the current claims, the instant specification, or the prior art. Thusly, a person of ordinary skill in the art would not be appraised of the metes and bounds of the scope of the claim with regard to this term as it is not clear what limitation “plane” imposes on the culture, if any. Claims 8 and 9 are included in this rejection for depending from indefinite claim 7.
Claim 12 recites the term “base medium,” which is not defined in the current claims, the instant specification, or the prior art. Thusly, a person of ordinary skill in the art would not be appraised of the metes and bounds of the scope of the claim with regard to this term as it is not clear what limitation “base” imposes on the medium, if any.
Claim 13 recites the term “embryonic ovarian somatic cell-like cells”, which is not clearly defined in the current claims, the instant specification, or the prior art. Thus, a person of ordinary skill in the art would not be appraised of the metes and bounds of the scope of the claim with regard to this term as it is not clear what limitation “embryonic” imposes on the ovarian somatic cell-like cells, if any.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638