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 .
Status of the Claims
Claims 1-16, 23, 25, and 28-29 are pending.
Claims 1-16, 23, 25, and 28-29 have been examined on their merits.
Claim Objections
Claim 13 is objected to for the following informalities: claim 13 recites “RA” which is an abbreviation for retinoic acid. Abbreviated terms should be spelled out in their first instance. Amending the claim to “retinoic acid (RA)” would be ameliorative.
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 16, 23, 25, and 28-29 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.
Claims 16, 25, and 28-29 recites the limitation “the artificial Sertoli” cells/cell. There is insufficient antecedent basis for this limitation in the claims because they are derived from claim 7 which is limited to only Sertoli cells. For compact prosecution, the “artificial” Sertoli cells have been interpreted to be synonymous with the Sertoli cells in claim 7.
Claim 23 recites the limitation “preferably”. A claim may be rendered indefinite by reference to subjective term (see MPEP 2173.05(b)(IV)). Specifically, the phrase “preferably” is a subjective term which renders the claim indefinite. The phrase "preferably" is not defined by the claim, the specification does not provide a standard for some standard for measuring the scope of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). Claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)); see also Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1373, 112 USPQ2d 1188 (Fed. Cir. 2014) (holding the claim phrase "unobtrusive manner" indefinite because the specification did not "provide a reasonably clear and exclusive definition, leaving the facially subjective claim language without an objective boundary”).
For example, in Datamize, the invention was directed to a computer interface screen with an "aesthetically pleasing look and feel." Datamize, 417 F.3d at 1344-45. The meaning of the term "aesthetically pleasing" depended solely on the subjective opinion of the person selecting features to be included on the interface screen. Nothing in the intrinsic evidence (e.g., the specification) provided any guidance as to what design choices would result in an "aesthetically pleasing" look and feel. Id. at 1352. The claims were held indefinite because the interface screen may be "aesthetically pleasing" to one user but not to another. Id. at 1350. See also Ex parte Anderson, 21 USPQ2d 1241 (Bd. Pat. App. & Inter. 1991) (the terms "comparable" and "superior" were held to be indefinite in the context of a limitation relating the characteristics of the claimed material to other materials).
During prosecution, the applicant may overcome a rejection by amending the claim to remove the subjective term, or by providing evidence that the meaning of the term can be ascertained by one of ordinary skill in the art when reading the disclosure. However, "[f]or some facially subjective terms, the definiteness requirement is not satisfied by merely offering examples that satisfy the term within the specification." DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1261, 113 USPQ2d 1097, 1108 (Fed. Cir. 2014).
For compact prosecution, the term has been interpreted as being optional.
Appropriate clarification is required.
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 (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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5, 7, 10-11, 15-16, 25, and 28-29 are rejected under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by Lee et al. (US2020239853, on IDS 11/14/2025).
In regards to claims 1, 7, 10, 15, Lee discloses methods for producing “Sertoli-like” (which have the same characteristics as Sertoli cells, paragraph [0015]) from stem cells (Abstract; claim 1), including embryonic stem cells (ESCs) specifically (claim 8), which are type of pluripotent stem cell (paragraph [0013]). In specific embodiments, Lee discloses that the ESCs may be derived from mouse (claim 9), which is a vertebrate.
Lee discloses that the Sertoli cells are derived by culturing intermediate mesoderm comprising FGF9 (paragraph [0012]; Fig. 6). Lee discloses that the medium can comprise insulin (paragraph [0037]). Lee discloses that the medium may be any conventional medium such as DMEM (paragraph [0031]), which is a well-known basal medium.
In regards to contacting genital ridge cells specifically, since the genital ridge is the developmental structure between intermediate mesoderm (see instant Fig. 1), because Lee discloses that intermediate mesoderm cells differentiate to Sertoli cells by being contacted with FGF9, which are ultimately derived from progenitor stem cells, genital ridge cells must both have been derived and contacted during this time.
In regards to claims 5 and 11, Lee discloses that the Sertoli cell differentiation step can comprise FSH in the base medium comprising FGF9 (Fig. 6; paragraph [0012]).
In regards to claim 16, Lee discloses that the Sertoli cells express at least SOX9 (Fig. 6).
In regards to claim 25, Lee discloses that the Sertoli cells may be cultured under conditions to form cell aggregates with tube-like structures (i.e., organoids) (paragraph [0041]).
In regards to claim 28, Lee discloses that the Sertoli cells can be isolated (claim 10).
In regards to claim 29, Lee discloses that the Sertoli cells can be transplanted (paragraphs [0058, 0062, 0085]
Therefore, Lee anticipates the invention as claimed.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 4, 6, 8, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US2020239853, on IDS 11/14/2025) in view of Watanabe et al. (Nature Biotechnology, 2007) and Knarston et al. (Stem Cell Reports, 2020).
Lee anticipates claims 1 and 7 as discussed above.
In regards to claims 2 and 8, for the differentiation of intermediate mesoderm, Lee teaches that the pluripotent stem cell as first cultured in a medium comprising CHIR99021 for about three days (claims 3 and 4, step (a); paragraph [0018]; Fig. 1), which is at least close to a timing of about day 4 (i.e., 4 days ± 12 hours, see instant specification paragraph [0071]; see MPEP 2144.05, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. “The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.”).
Following this, Lee teaches that the medium comprising CHIR99021 is replaced with a medium comprising bFGF for about 2 to 5 days (claims 3 and 4, step (b); paragraph [0018]; Fig. 1), which overlaps with the timing of about day 4 to about day 7.
In regards to differentiating into presomitic mesoderm cells, similar to as above, since presomitic mesoderm is a developmental stage between pluripotent stem cells and intermediate mesoderm, because Lee differentiates pluripotent stem cells to intermediate mesoderm, there must have been a presomitic mesoderm during this time.
Following this, Lee teaches that the medium is changed and cells further differentiated to Sertoli cells (see as in claim 1 above; Lee Fig. 6).
The difference then is that Lee does not specifically teach a step of providing the pluripotent stem cells in a ROCK inhibitor, and subsequently removing that ROCK inhibitor, and Lee uses bFGF, not FGF9 and does not explicitly teach heparin in the second intermediate differentiation medium.
However, a person of ordinary skill in the art would have been motivated to contact pluripotent stem cells with a ROCK inhibitor in order to suppress dissociation-induced apoptosis and increase cloning efficiency as taught by Watanabe (Title, Abstract, p681). They would have been motivated to remove a ROCK inhibitor when the reagent is not needed in order to save on reagents and costs. Furthermore, because Watanabe teaches that a ROCK inhibitor can be used to promote pluripotent stem cell survival and dissociation in vitro (Title, Abstract, p681; Fig. 1, p682), it could have been done with predictable results and a reasonable expectation of success.
In regards to FGF9 and heparain, a person of ordinary skill in the art would have been motivated to add these reagents because Knarston teaches that they are effective for optimization for the differentiation of intermediate/lateral plate mesoderm for the differentiation of Sertoli cells from pluripotent stem cells ((Title, Summary, p1377; Fig. 2, p1380; Fig. 3, p1382; Fig. 4, p1383-1384). Furthermore, because Knarston teaches that FGF9 and heparin can be used for the differentiation of pluripotent stem cells ((Title, Summary, p1377; Fig. 2, p1380; Fig. 3, p1382; Fig. 4, p1383-1384; Experimental Procedures, p1388) and because Lee and Knarston are in the same technical field of differentiating Sertoli cells from pluripotent stem cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 4, Lee does not explicitly teach differentiating Sertoli cells with BMP4. However, a person of ordinary skill in the art would have been motivated to add BMP4 because Knarston teaches that CHIR induction followed by addition of FGF9 and BMP4 improves expression testis markers (p1381; Fig. 3, p1382). Furthermore, because Lee teaches that Sertoli cells can be differentiated in media comprising FGF9 with BMP4, it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 6 and 12, Lee silent to whether the pluripotent stem cells are human pluripotent stem cells. However, a person of ordinary skill in the art would have been motivated to use human embryonic stem cells in order to better understand human biology and because it would be most relevant to human health. Furthermore, because Knarston teaches that human pluripotent stem cells can be used to induce Sertoli cells in vitro (Title, Abstract, p1377), a person of ordinary skill in the art could have used human embryonic stem cells specifically, with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lee, Watanabe, and Knarston renders the invention unpatentable a claimed.
Claims 3, 9, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US2020239853, on IDS 11/14/2025) in view of Rore et al. (Communications Biology, 2021).
Lee anticipates claims 1 and 7 as discussed above.
In regards to claims 3, 9, and 23, Lee teaches that final Sertoli differentiation step can occur on day 7 (paragraph [0018]). Lee also teaches that media be replaced (paragraph [0018]).
In regards to the medium, as above. Lee teaches that it may comprise FGF9 and insulin (paragraphs [0012, 0037]; Fig. 6).
While Lee does not explicitly teach that the medium comprises IGF1, a person of ordinary skill in the art would have been motivated to include IGF1 because Rore teaches that IGF1 is known to stimulate proliferation of Sertoli cells (Results, p2) and promotes development of Sertoli cell populations (Fig. 1, p3-4; Discussion, p10). Furthermore, because Rore teaches that it is known in the art that IGF1 has a proliferative effect on Sertoli cells and promotes their development, it could have been done with predictable results and a reasonable expectation of success.
In regards to “artificial” Sertoli cells, the disclosure does not define this term (and it is not a term in the art) and therefore, has broadly interpreted as the resultant cells of these method steps. Therefore, since Lee as modified teaches these steps the Sertoli cells of Lee would also be “artificial.”
Therefore, the combined teachings of Lee and Rore renders the invention unpatentable a claimed.
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US2020239853, on IDS 11/14/2025) in view of Hayashi et al. (Cell, 2011, on IDS 11/14/2025) and Rore et al. (Communications Biology, 2021).
Lee anticipates claims 1 and 7 as discussed above.
In regards to claim 13, Lee teaches that pluripotent stem cells are maintained in a medium comprising LIF (paragraph [0095]). Following this, as above, Lee teaches that the cells are differentiated into intermediate mesoderm in a medium comprising bFGF and retinoic acid (RA) (claims 3 and 4, step (b); paragraphs [0018, 0036]; Fig. 1).
While Lee does not specifically teach culturing the cells with Activin A, a person of ordinary skill in the art would have been motivated to add Activin A because Hayashi teaches that Activin A in combination with bFGF, after initial treatment with LIF promotes epiblast differentiation which can then differentiate to primordial germ cell-like cells with the capacity for spermatogenesis (Abstract, p519; Fig. 1, p521). Hayashi teaches that cells are contacted over a span of about three days (Fig. 1, p521) which is close to the timings as in claim 13.
Moreover, a person of ordinary skill in the art would have been motivated to obtain epiblast cells because as taught by Rore, the co-culturing of testicular somatic cells, including Sertoli cells with epiblast cells results in self-organized aggregates which form self-organized testicular organoids that comprise gonocyte-like cells that are enclosed within a seminiferous tubule-like structure composed of Sertoli cells (Abstract, p1).
Furthermore, because Hayashi demonstrates that these cells can be differentiated in media comprising Activin A and FGFb after initial culturing in LIF (Fig. 1, p521), and because Lee, Rore, and Hayashi are in the same technical field of differentiating male reproductive cells (indeed Rore cites Hayashi directly, see Differentiation of EpiLCs and PGCLCs, p10), it could have been done with predictable results and a reasonable expectation of success.
In regards to the steps of adding reagents, i.e., adding media comprising Activin A and bFGF for about two days and then replacing it with media comprising Activin A and RA after two days, according to MPEP 2144.04, changes to the sequence of adding ingredients is prima facie obvious absent new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); see also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps; in re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious).
In the instant case, the reagents (ingredients) were all taught by the art, and the result, differentiation of epiblast cells, is the same.
In regards to claim 14, as above, Lee teaches that pluripotent stem cells are maintained in a medium comprising LIF (paragraph [0095]). Following this, as above, Lee teaches that the cells are differentiated into intermediate mesoderm in a medium comprising bFGF and retinoic acid (RA) (claims 3 and 4, step (b); paragraphs [0018, 0036]; Fig. 1).
While Lee does not specifically teach culturing the cells with Activin A, a person of ordinary skill in the art would have been motivated to add Activin A because Hayashi teaches that Activin A in combination with bFGF, after initial treatment with LIF promotes epiblast differentiation which can then differentiate to primordial germ cell-like cells with the capacity for spermatogenesis (Abstract, p519; Fig. 1, p521). Hayashi teaches that cells are contacted over a span of about three days (Fig. 1, p521) which is close to the timings as in claim 13.
Moreover, a person of ordinary skill in the art would have been motivated to obtain epiblast cells because as taught by Rore, the co-culturing of testicular somatic cells, including Sertoli cells with epiblast cells results in self-organized aggregates which form self-organized testicular organoids that comprise gonocyte-like cells that are enclosed within a seminiferous tubule-like structure composed of Sertoli cells (Abstract, p1).
As above, regards to “artificial” Sertoli cells, the disclosure does not define this term (and it is not a term in the art) and therefore, has broadly interpreted as the resultant cells of these method steps. Therefore, since Lee as modified teaches these steps the Sertoli cells of Lee would also be “artificial.”
Furthermore, because Hayashi demonstrates that these cells can be differentiated in media comprising Activin A and FGFb after initial culturing in LIF (Fig. 1, p521), and because Lee, Rore, and Hayashi are in the same technical field of differentiating male reproductive cells (indeed Rore cites Hayashi directly, see Differentiation of EpiLCs and PGCLCs, p10), it could have been done with predictable results and a reasonable expectation of success.
In regards to the steps of adding reagents, i.e., adding media comprising Activin A and bFGF for about two days and then replacing it with media comprising Activin A and RA after two days, according to MPEP 2144.04, changes to the sequence of adding ingredients is prima facie obvious absent new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946); see also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps; in re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious).
In the instant case, the reagents (ingredients) were all taught by the art, and the result, differentiation of epiblast cells, is the same.
In regards to IGF1, as above, a person of ordinary skill in the art would have been motivated to include IGF1 because Rore teaches that IGF1 is known to stimulate proliferation of Sertoli cells (Results, p2) and promotes development of Sertoli cell populations (Fig. 1, p3-4; Discussion, p10). Furthermore, because Rore teaches that it is known in the art that IGF1 has a proliferative effect on Sertoli cells and promotes their development, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lee, Hayashi, and Rore renders the invention unpatentable a claimed.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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