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 .
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/QA2022/050001, filed
07 February 2022. Acknowledgment is made of Applicant’s claim for benefit under 35 USC 119(e) to US Provisional Application No. 63146930, filed 08 February 2021.
Status of the Claims
Applicant’s preliminary submission filed 08 August 2023 has been entered. Claims 18-37 are pending. Claims 1-17 have been cancelled without prejudice or disclaimer and claims 18-37 have been newly added. Therefore, prosecution on the merits commences for claims 18-37.
Specification
The substitute Specification filed 08 August 2023 is acknowledged and entered into the application file.
Claim Interpretation
Instant claim 29 is directed to induced pluripotent stem cells (iPSCs) from patients with mutations in a gene encoding glucokinase (GCK), made by a method comprising:
a) obtaining peripheral blood mononuclear cells (PBMCs) of patients with mutations in the GCK gene, wherein heterozygous mutations in the GCK gene cause maturity-onset diabetes of the young type 2 (MODY2), and homozygous mutations in the GCK gene cause permanent neonatal diabetes mellitus (PNDM);
b) identifying heterozygous or homozygous mutations in the GCK gene in the PBMCs using whole exome sequencing (WES);
c) confirming the heterozygous or homozygous mutations in the GCK gene in the PBMCs using Sanger sequencing;
d) reprogramming the PBMCs into the iPSC lines;
e) selecting and expanding the reprogrammed iPSC lines;
f) confirming the heterozygous or homozygous mutations in the GCK gene in the iPSC lines using Sanger sequencing; and
g) confirming the expression of pluripotency markers in the iPSC lines.
This is a product-by-process claim. Product-by-process claims are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the production method imparts any particular structure or significance to the iPSCs, other than the iPSCs comprising a mutation in the GCK gene. Thus, the claim will be interpreted as if GCK-mutated iPSCs derived from any source or production method fulfills the recited claim limitation. See MPEP § 2113.
In addition, instant claims 19-20 and 30 recite intended use limitations. Intended use limitations are considered only in so far as they physically limit the claimed iPSCs. Therefore, so long as the generated iPSCs are physically capable of being configured for use as pancreatic beta-cells and in transplantation therapy, they will read on the claims as written.
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 19-28 and 30-37 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.
Regarding claim 19: The instant claim is dependent upon cancelled claim 1. This therefore renders the claim indefinite.
In addition, the term “normal” in the instant claim is a relative term which renders the claim indefinite. The term “normal” 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. More specifically, the only reference to “normal” in relation to the pancreatic beta-cells is within Paragraph [0021] of the instant Specification filed 08 August 2023, and is a mere recitation of the embodiment. Therefore, the ordinary artisan would not be readily apprised of the metes and bounds of the claim, as they will not be able to readily determine what is considered a “normal” pancreatic beta-cell, thus rendering the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claim will be interpreted as depending from independent claim 18.
Regarding claim 20: The instant claim is dependent upon cancelled claim 2. This therefore renders the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claim will be interpreted as depending from instant claim 19.
Regarding claims 21-27: The instant claims are each dependent upon cancelled claim 1 or 4. This therefore renders each claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claims will be interpreted as depending from independent claim 18.
Regarding claim 28: The instant claim is dependent upon cancelled claim 1. This therefore renders the claim indefinite.
In addition, the instant claim recites the limitation “brachyury (T)”. While parentheticals can be used as abbreviations, the use of parentheticals adjacent to terms which recite alternate names or isoforms renders the claim indefinite because it is not clear whether the items within the parentheticals are required or optional.
Appropriate correction is required.
For the sake of compact prosecution, the instant claim will be interpreted as depending from instant claim 18.
Regarding claim 30: The instant claim is dependent upon cancelled claim 12. This therefore renders the claim indefinite.
In addition, the term “normal” in the instant claim is a relative term which renders the claim indefinite. The term “normal” 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. More specifically, the only reference to “normal” in relation to the pancreatic beta-cells is within Paragraph [0021] of the instant Specification filed 08 August 2023, and is a mere recitation of the embodiment. Therefore, the ordinary artisan would not be readily apprised of the metes and bounds of the claim, as they will not be able to readily determine what is considered a “normal” pancreatic beta-cell, thus rendering the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claim will be interpreted as depending from independent claim 29.
Regarding claims 31-37: The instant claims are each dependent upon cancelled claim 12 or 14. This therefore renders each claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claims will be interpreted as depending from independent claim 29.
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 18-37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aqel et al (Stem Cell Res, 2020, of record on IDS filed 08 August 2023).
It is of note that Aqel et al name multiple authors – two of which are the joint inventors of the instant application – and was published within one year of the effective filing date of the instant application. See MPEP § 717 and MPEP § 2153.01.
Aqel et al disclose a method for the generation of induced pluripotent stem cells (iPSCs) from patients with a mutation in the glucokinase (GCK) gene, wherein the method comprises: a) obtaining PBMCs from the patient having either a homozygous or heterozygous mutation in the GCK gene, resulting in either permanent neonatal diabetes mellitus or maturity-onset diabetes of the young type 2, respectively; b) identifying the GCK gene mutation within the PBMCs via whole exome sequencing; c) confirming the GCK gene mutation in the PBMCs via Sanger sequencing; d) reprogramming the PBMCs into iPSCs; e) selecting and expanding the reprogrammed iPSCs; f) confirming the GCK gene mutation in the reprogrammed iPSCs via Sanger sequencing; and g) confirming expression of pluripotency markers in the iPSCs (Abstract; Page 2).
Aqel et al further disclose that the generated iPSCs express the pluripotency markers of OCT4, NANOG, SOX2, SSEA4, TRA-1-60, and TRA-1-81 (Page 2; Table 2; Figure 1).
Aqel et al further disclose that the generated iPSCs spontaneously form embryoid bodies and express specific markers of the three germ layers, including NESTIN and NEUROd1 (ectoderm), brachyury (mesoderm), and SOX17 (endoderm) (Page 2; Figures 1G, H).
Accordingly, Aqel et al anticipate the claims as follows:
Regarding claims 18 and 29: Aqel et al disclose a method for the generation of induced pluripotent stem cells (iPSCs) from patients with a mutation in the glucokinase (GCK) gene, wherein the method comprises: a) obtaining PBMCs from the patient having either a homozygous or heterozygous mutation in the GCK gene, resulting in either permanent neonatal diabetes mellitus or maturity-onset diabetes of the young type 2, respectively; b) identifying the GCK gene mutation within the PBMCs via whole exome sequencing; c) confirming the GCK gene mutation in the PBMCs via Sanger sequencing; d) reprogramming the PBMCs into iPSCs; e) selecting and expanding the reprogrammed iPSCs; f) confirming the GCK gene mutation in the reprogrammed iPSCs via Sanger sequencing; and g) confirming expression of pluripotency markers in the iPSCs. This therefore reads on the method of instant claim 18 and produced iPSCs of instant claim 29.
Regarding claims 19-20 and 30: As aforementioned in the discussion of claims 18 and 29, Aqel et al disclose iPSCs comprising a mutation in the GCK gene. As the iPSCs are physically capable, or suitable, for use as pancreatic beta-cells (claims 19, 30) and in transplantation therapy (claims 20, 30), this therefore anticipates the method and iPSCs of the instant claim for the same reasons as discussed in the rejection of instant claims 18 and 29. See Claim Interpretation section for the discussion of the intended use limitation.
Regarding claims 21-27 and 31-37: Following the discussion of claims 18 and 29, Aqel et al further disclose that the generated iPSCs express the pluripotency markers of OCT4 (claims 21-22, 31-32), NANOG (claims 23, 33), SOX2 (claims 24, 34), SSEA4 (claims 27, 37), TRA-1-60 (claims 25, 35), and TRA-1-81 (claims 26, 36). This therefore reads on the method and iPSCs of the instant claims.
Regarding claim 28: Following the discussion of claim 18, Aqel et al further disclose that the generated iPSCs spontaneously form embryoid bodies and express specific markers of the three germ layers, including NESTIN and NEUROd1 (ectoderm), brachyury (mesoderm), and SOX17 (endoderm). This therefore reads on the method of the instant claim.
Claims 29-37 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Hua et al (US 2014/0242038 A1, of record on IDS filed 08 August 2023).
Hua et al disclose methods for generating pancreatic progenitor cells, insulin producing cells or endoderm cells using induced pluripotent stem cells (Abstract).
As such, Hua et al disclose induced pluripotent stem cells (iPSCs) having a missense mutation in the GCK gene that are derived from patients suffering from MODY2 (Paragraphs [0025], [0131], [0181]-[0192], [0261]-[0302]; Figure 4).
Hua et al further disclose that the GCK-mutated iPSCs express the pluripotency markers of OCT4, NANOG, SOX2, TRA-1-60, and SSEA4 (Paragraphs [0022], [0293], [0351]; Figures 1D, 4, 11A-F, 23).
Hua et al further disclose that the GCK-mutated iPSCs can be differentiated into pancreatic beta-cells and therapeutically transplanted into immunocompromised mice (Paragraphs [0026]-[0027], [0184], [0222]-[0223], [0295]; Figures 5-6).
Accordingly, Hua et al anticipate the claims as follows:
Regarding claim 29: The instant claim comprises product-by-process language. The effect of the product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety.
Accordingly, Hua et al disclose iPSCs having a missense mutation in the GCK gene that are derived from patients suffering from MODY2. This therefore reads on the iPSCs of the instant claim.
Regarding claim 30: Following the discussion of claim 29, Hua et al further disclose that the GCK-mutated iPSCs can be differentiated into pancreatic beta-cells and therapeutically transplanted into immunocompromised mice. This therefore reads on the iPSCs of the instant claim.
Regarding claims 31-35 and 37: Following the discussion of claim 29, Hua et al further disclose that the GCK-mutated iPSCs express the pluripotency markers of OCT4 (claims 31-32), NANOG (claim 33), SOX2 (claim 34), TRA-1-60 (claim 35), and SSEA4 (claim 37). This therefore reads on the iPSCs of the instant claims.
Regarding claim 36: Following the discussion of claim 29, Hua et al further disclose that the GCK-mutated iPSCs are differentiated from patient-derived fibroblasts using the CytoTune™-iPS Sendai Reprogramming Kit (Paragraph [0284]).
Hua et al further disclose that Wolfram iPSCs are differentiated from patient-derived fibroblasts using the CytoTune™-iPS Sendai Reprogramming Kit (Paragraph [0403]). It is of note that the Wolfram iPSCs are derived from patients suffering from Wolfram syndrome that have a mutation in the WFS1 gene, which is characterized by juvenile-onset diabetes (Paragraph [0134]). Hua et al further disclose that the Wolfram iPSCs express the pluripotency markers of SSEA4, SOX2, TRA-1-60, NANOG, TRA-1-81, and OCT4 (Paragraphs [0049], [0407]; Figures 28A-D).
Therefore, as the same reprogramming kit is utilized for the GCK-mutated iPSCs and Wolfram iPSCs, the GCK-mutated iPSCs will inherently also express the pluripotency marker of TRA-1-81, which reads on the iPSCs of the instant claim. See MPEP § 2112.
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 18-27 and 29-37 are rejected under 35 U.S.C. 103 as being unpatentable over Hua et al (US 2014/0242038 A1, of record on IDS filed 08 August 2023) in view of Santostefano et al (Lab Invest, 2014).
Hua et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Santostefano et al is considered prior art under 35 USC 102(a)(1). Hua et al anticipate instants claim 29-37 based on the Claim Interpretation section above. However, the following rejection relies on an alternative interpretation wherein the production method of instant claim 29 does impose significant structural or functional characteristics to the generated iPSCs.
Regarding claims 18 and 29: Hua et al disclose methods for generating pancreatic progenitor cells, insulin producing cells or endoderm cells using induced pluripotent stem cells (Abstract).
As such, Hua et al disclose the generation of induced pluripotent stem cells (iPSCs) having a missense mutation in the GCK gene that are derived from patients suffering from MODY2, wherein: primary fibroblasts are first isolated from the MODY2 patients; the mutations are confirmed with exonic sequencing of the GCK gene; the fibroblasts are reprogrammed into iPSCs and expanded; and the generated GCK-mutated iPSCs are confirmed for pluripotency (Paragraphs [0025], [0131], [0181]-[0192], [0194]-[0195], [0261]-[0302]; Figure 4).
Hua et al further disclose that Sanger sequencing is utilized to analyze GCK gene mutation sites within the cells (Paragraphs [0028]).
Hua et al do not disclose that the starting population of cells is peripheral blood mononuclear cells, as required by instant claims 18 and 29.
Santostefano et al, however, disclose that dermal fibroblasts and PBMCs are the most common starting cells when generating iPSCs (Page 8, Practical considerations).
Therefore, it would have been prima facie obvious to modify the method of Hua et al such that the starting population of cells from the MODY2 patients is PBMCs, as disclosed in Santostefano et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize a starting population of PBMCs, as the isolation of PBMCs from the patient is less invasive and requires less processing time that dermal fibroblasts (Santostefano et al: Page 8), and would have had a reasonable expectation of success given that it is not outside the skillset of the ordinary artisan to adapt the differentiation protocols for PBMCs versus dermal fibroblasts (Santostefano et al: Page 8). See MPEP § 2143(I)(G).
Consequently, Hua et al as modified by Santostefano et al render obvious a method of generating GCK-mutated iPSCs, the method comprising: isolated PBMCs from MODY2 patients (instant step a); the mutations are confirmed with exonic sequencing of the GCK gene (instant step b); the fibroblasts are reprogrammed into iPSCs (instant step d) and expanded (instant step e); and the generated GCK-mutated iPSCs are confirmed for pluripotency (instant step g). As the ordinary artisan would recognize that the Sanger sequencing can be utilized to analyze and confirm the GCK mutation sites in both the starting population of PBMCs (instant step c) and generated iPSCs (instant step f), this therefore renders obvious the method of instant claim 18 and generated iPSCs of instant claim 29.
Regarding claims 19-20 and 30: Following the discussion of claims 18 and 29, Hua et al further disclose that the GCK-mutated iPSCs can be differentiated into pancreatic beta-cells (claims 19, 30) and therapeutically transplanted into immunocompromised mice (claims 20, 30) (Paragraphs [0026]-[0027], [0184], [0222]-[0223], [0295]; Figures 5-6). This therefore reads on the instant claims.
Regarding claims 21-25, 27, 31-35, and 37: Following the discussion of claims 18 and 29, Hua et al further disclose that the GCK-mutated iPSCs express the pluripotency markers of OCT4 (claims 21-22, 31-32), NANOG (claim 23, 33), SOX2 (claim 24, 34), TRA-1-60 (claim 25, 35), and SSEA4 (claim 27, 37) (Paragraphs [0022], [0293], [0351]; Figures 1D, 4, 11A-F, 23). This therefore reads on the instant claims.
Regarding claims 26, 36: Following the discussion of claims 18 and 29, Hua et al further disclose that the GCK-mutated iPSCs are differentiated from patient-derived fibroblasts using the CytoTune™-iPS Sendai Reprogramming Kit (Paragraph [0284]).
Hua et al further disclose that Wolfram iPSCs are differentiated from patient-derived fibroblasts using the CytoTune™-iPS Sendai Reprogramming Kit (Paragraph [0403]). It is of note that the Wolfram iPSCs are derived from patients suffering from Wolfram syndrome that have a mutation in the WFS1 gene, which is characterized by juvenile-onset diabetes (Paragraph [0134]). Hua et al further disclose that the Wolfram iPSCs express the pluripotency markers of SSEA4, SOX2, TRA-1-60, NANOG, TRA-1-81, and OCT4 (Paragraphs [0049], [0407]; Figures 28A-D).
Therefore, as the same reprogramming kit is utilized for the GCK-mutated iPSCs and Wolfram iPSCs, the GCK-mutated iPSCs will inherently also express the pluripotency marker of TRA-1-81 (claims 26, 36). See MPEP § 2112. This consequently reads on the instant claims.
Claims 18-37 are rejected under 35 U.S.C. 103 as being unpatentable over Hua et al (US 2014/0242038 A1, of record on IDS filed 08 August 2023) in view of Santostefano et al (Lab Invest, 2014), and further in view of Soejitno et al (Ther Adv Endocrinol Metab, 2011).
The discussion of Hua et al as modified by Santostefano et al regarding claim 18 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Hua et al anticipate claims 29-37. Hua et al as modified by Santostefano et al render obvious claims 18-27 and 29-37. Soejitno et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 28: Following the discussion of claim 19, Hua et al further disclose that the GCK-mutated iPSCs spontaneously differentiate into embryoid bodies that contain cell types of the three germ layers: endoderm, mesoderm, and ectoderm (Paragraphs [0025], [0149], [0183], [0198], [0216]; Figure 4).
The combination of Hua et al and Santostefano et al do not teach that the germ layer markers are NESTIN, NEUROD1, brachyury, and SOX17, as required by instant claim 28.
Soejitno et al, however, disclose that iPSCs spontaneously aggregate into an embryoid body and express the germ line gene markers of SOX17, Brachyury-T, and NESTIN, and NEUROD1 (Pages 198-199).
Therefore, it would have been prima facie obvious to have modified the method of Hua et al in view of Santostefano et al such that the generated embryoid bodies express all of SOX17, Brachyury-T, and NESTIN, and NEUROD1, as detailed in Soejitno et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to generate embryoid bodies that express markers of all three germ lines, as it indicates that the embryoid bodies have the potential to differentiate into cells of the ectoderm, mesoderm, or endoderm and serve as a therapeutic for those tissues (Hua et al: Paragraphs [0149], [0268]), and would have had a reasonable expectation of success given that the disclosures of Hua et al and Soejitno et al are both concerned with the generation of tri-lineage embryoid bodies from iPSCs. See MPEP § 2143(I)(G).
Consequently, Hua et al as modified by Santostefano et al and Soejitno et al render obvious a method of producing GCK-mutated iPSCs, wherein the iPSCs spontaneously differentiate into embryoid bodies expressing the germ line gene markers of SOX17, Brachyury-T, and NESTIN, and NEUROD1. This therefore renders obvious the method of the instant claim.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633