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 .
Response to Arguments
The Applicant has provided amendments, and arguments, in response to the previous Office Action. The Applicant’s amendments have provided for a withdrawal of the previous objections to the claims and 35 USC 112(b) rejections. With respect to trace elements a, b, and c, the Applicant has assured the Office that these would be well-known to the ordinary artisan, and do not include trademarked material.
Based upon the Applicant’s amendments, and arguments, the previous 35 USC 102 rejections have modified. Now, all claims are rejected under 35 USC 103. The Examiner’s response to the Applicant’s arguments, and updated rejections, will be provided in the following paragraphs.
On page 10 of the Applicant’s Arguments, the Applicant appears to suggest that Jeon implicitly teaches away from the claimed combination; the Applicant asserts that Jeon teaches PDMS substrate to specifically maintain the cells in an undifferentiated state. When looking at Jeon, and the figure specifically cited by the Applicant, it appears that Jeon only teaches that PDMS inhibits spontaneous differentiation, whereas there is no mention that it inhibits directed differentiation when provide with a differentiation medium. Since Jeon does not appear to test PDMS with a differentiation medium, there is no clear connection that PDMS inhibits differentiation, and as such, there is no teaching away from using a soft/patterned PDMS substate. This is further underscored by Milman, who does not teach the substrate material, and appears to suggest that biochemical signaling is needed to induce an endodermal lineage, and not necessarily substrate stiffness. See page 19, lines 19-25.
With respect to the Non-Statutory Double Patenting Rejection, it appears as though the co-pending claims continue to read upon the instant claims, and as such, the rejection is maintained.
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 and 21 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.
The term “soft” in claim 1 is a relative term which renders the claim indefinite. The term “soft” 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. Soft is a relative term, and it is unclear what the intended scope should be; prior to amending, the claim that recited “soft” provided a measure of hardness in a parenthetical statement (canceled claim 8). For the sake of examining the claim on its merit, it will be assumed that this is the claimed range; however, the Applicant should include this range in the claims.
Claim 21 provides for reducing the volume of media during stage 5. It is unclear what this reduction is relative to. For example, there is no clear volume provided for any of the stages, and as such, it is unclear to what degree the volume should be reduced to, and still be within the scope of the invention.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-4, 9-16, 20, and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Milman, et al (WO 2019/222487 [IDS Reference]) and Jeon, et al (Biomaterials, 33, 5206-5202, 2012). Milman provides for a method of producing insulin-producing β-cells in a suspension. Milman provides stem cells and serum-free media; the cells are contacted with TGFβ/activin or GSK synthase for a time sufficient to form definitive endoderm; the definitive endoderm is contacted with an FGFR2b agonist for a sufficient time to form primitive gut tube; these cells are contacted with a RAR agonist for a sufficient time to produce early pancreas progenitor cells; these cells are incubated for at least 3 days, for a time sufficient to form pancreatic progenitor cells; contacting these cells with an Alk5 inhibitor, a gamma secretase inhibitor, SANT1 , Erbbl (EGFR) or Erbb4 agonist, or a RAR agonist for an amount of time sufficient to form an endoderm cell; finally, allowing these cells to mature in serum-free media for an amount of time sufficient to form β-cells. See pages 35-39 and claim 1. Milman does not teach soft PDMS or micron sized dots; however, Milman does note that biochemical signaling is a greater driver of directed differentiation into an endodermal lineage, and not necessarily substrate stiffness. See page 19, lines 19-25.
Milman does not teach that the stem cells can be cultured on micron-sized dots or on soft PDMS, but it is well-known to those of ordinary skill in the art that the microenvironment a cell is cultured in will affect the stemness and differentiation of the cells. Jeon provides for methods of culturing stem cells on PDMS micro- and nano-patterned dots, and further notes that these culture methods could be used to improve the expansion of the stem cells, prior to differentiation. See page 1, “Introduction” section; page 5215, “Discussion” section. Based upon Jeon, it would be clear that an undifferentiated cell can be expanded on the substrate, without risk of the cell spontaneously differentiating. See page 5217, Figure 1a. Additionally, Jeon notes that the method of using the claimed substrate would potentially lead to a homogenous stem cell source that can potentially have a “higher differentiation potential. See page 5215, left column, 2nd paragraph. This would suggest to the ordinary artisan that the cell can be infinitely expandable on this substrate, without any spontaneous differentiation, then it can be efficiently differentiated into the cell-line that was chosen by the ordinary artisan. Since there is a clear implicit motivation to apply stem cells to PDMS microdots, and their application to this culture-type would be highly predictable, it would be obvious to the ordinary artisan to modify Milman with the culture methods of Jeon.
With respect to claim 1, Milman teaches every claim limitation, in the same order as that claimed. Jeon suggests that the claimed substrate is useful for expanding undifferentiated stem cells, then states that the resulting cells would have higher differentiation potential.
With respect to claim 2, Milman teaches reaggregating clusters. See page 2, lines 28-30.
With respect to claim 3, although Milman does not explicitly state cryopreservation, Milman does suggest that the method provide for a stable formulation that can be stored at a “convenient temperature.” See page 23, line 18. Although not explicitly stated, the ordinary artisan is fully aware of the utility of cryopreserving cells. Additionally, the claim does not provide for any nonconventional cryopreservation methods. As such, it would be obvious to cryopreserve the cells of Milman is a routine manner, and reasonably expect that most of the cells will be functional upon restoring their temperature to a physiological level.
With respect to claims 4 and 9, Milman specifically provides for an applied example for controlling the physical microenvironment. See page 61, Example 2.
With respect to claim 10, Milman provides the β-cells on beads. See page 49, first line.
With respect to claim 11, Milman teaches the same additions. See page 2, lines 24-27.
With respect to claims 12 and 13, Milman teaches an identical method that results in the same cells. As such, Milman must have also provided for the same “sufficient time.”
With respect to claim 14, Milman indicates that the serum-free media can include FBS. See page 2, line 26.
With respect to claim 15, although Milman does not explicitly mention “lefty A,” Milman provides for an identical protocol that results in identical cells wherein “latrunculin A” is used. See page 66, lines 15-33. As such, it appears as though Milman uses “latruculin A,” which is the same as “lefty A.”
With respect to claim 16, although Milman suggest the inclusion of Alk5i, the claimed amount is not described. See page 2, line 23. Since it is clear that the ordinary artisan’s goal is to generate insulin producing β-cells, the optimization of this value would be routine; this would be considered routine because the goal is clear to the ordinary artisan, and providing multiple concentrations of Alk5i to various cultures, in order to find the greatest insulin producer, would be a conventional procedure for the ordinary artisan.
With respect to claim 20, Milman teaches Y27632 and blebbistatin. See page 3, line 21.
With respect to claim 25, Milman teaches this treatment. See page 5, lines 1-4.
With respect to claim 26, it appears as though Milman does not add this compound in the claimed step.
With respect to claim 27, Milman teaches insulin secretion with high glucose exposure. See page 9, line 33.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Milman, et al (WO 2019/222487 [IDS Reference]) Jeon, et al (Biomaterials, 33, 5206-5202, 2012) and Nyitray, et al (Tissue Engineering: Part A, 20, 1888-1895, 2014). See the discussion of Milman above. Although Milman does not describe plating the β-cells on microcontact printed patterns, Milman explicitly states that the microenvironment of cells strongly impacts their physiology. See page 61, second paragraph; page 62, first [incomplete] paragraph and second [full] paragraph (beginning “Cells can sense…”).
Nyitray provides for a microenvironment that is consistent with the claimed micropatterning and suggests that β-cells fate and insulin production can be enhanced by providing micropatterning. See page 1888, “Abstract” section; page 1894, “Conclusions” section.
Based upon the clear known and expected behavior that β-cells will be affected by their microenvironment, the ordinary artisan would be implicitly motivated to find a culture system that is an improvement over standard culturing. As such, it would be obvious to the ordinary artisan to search for β-cells culture methods that offer improve physiologically outcomes over the standard methods. The application of Nyitray’s culturing method on the β-cells of Milman would lead to predictable results.
Claims 7 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Milman, et al (WO 2019/222487 [IDS Reference]) and Nadri, et al (Artificial Cells, Nanomedicine, and Biotechnology, 46, S178-S187, 2018)). Milman does not teach culturing the stem cells on an electrospun scaffold. Nadri teaches the support of stem cells on electrospun fibers, and their ultimate differentiation into insulin producing cells. See page S178, “Abstract” section. Since it is clear that Nadri shows a differentiate route that can utilize the beginning cells of Milman and result in insulin producing cells shows that there is a clear predictability in that the ordinary artisan is equipped to provide electrospun fibers with stem cells, and differentiate these cells into insulin producing β-cells. It would be obvious to the ordinary artisan to apply the method of Nadri to that of Milman, because it appears that there would be a clear expectation that the method of Nadri would enhance the differentiation of the cells of Milman into insulin producing β-cells. Furthermore, Nadri notes that bFGF is one of several biomolecules that can be used to enhance the differentiation of cells to an insulin producing β-cell lineage. See page S184, third [full] paragraph.
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 9-16, 20, 25, 27, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13--19 of copending Application No. 17/055,946 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because application ‘946 provides for a disclosure and claim-set that anticipates the claims of the instant claim-set. For a detailed analysis of the similarities, see the 35 USC 102 rejection of claims 1, 2, 4, 9-15, 17-20, 25, 27, and 32 and the 35 USC 103 rejections of claims 3 and 16, with respect to Milman above. It is noted that the above-cited Milman is drawn to WO 2019/222467, but the cited application claims support from this document and provides for a claim-set that entirely reads upon the instantly claimed method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID W BERKE-SCHLESSEL whose telephone number is (571)270-3643. The examiner can normally be reached M-F 8AM-5:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID W BERKE-SCHLESSEL/Primary Examiner, Art Unit 1651
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