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 .
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.
Claim Status
Claims 24-52 are currently pending and examined on the merits.
Claim Objections
Applicant is advised that should claim 26 be found allowable, claim 51 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).
Information Disclosure Statement
Nine IDS were received on 9/25/24, 10/25/24, 11/22/24, 2/14/25, 5/20/25, 6/3/25, 9/12/25, 3/20/26, 6/10/26. All references have been considered; however, due to the voluminous number of references in the IDS they have been only briefly considered. It is noted that the cloaking of a relevant reference by inclusion in a long list of citations may not comply with the Applicant’s duty of disclosure. Penn Yan Boats, Inc. v. Sea Lark Boats, Inc., 359 F. Supp. 948 (S.D. Fla. 1972). Therefore, the applicant is encouraged to present a concise statement as to the relevance of any particular documents known to be material for patentability as defined by 37 C.F.R. § 1.56.
Claim Rejections - 35 USC § 103
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.
Claim(s) 24-37, 40-44, 46, 49-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bose et al., (2 Jan 2013) Human embryonic stem cell differentiation into insulin secreting β-cells for diabetes. Cell Biology International, 36(11): 1013-1020 (cited on IDS dated 9/25/24, hereinafter Bose).
Regarding claims 24, 26-27, 34, 49, 51, Bose discloses methods of differentiating human embryonic stem cells (ESCs) into insulin secreting BCs for the treatment of diabetes (Abstract). Bose explains that diabetes is the most common metabolic disease in the world but that there are limited methods for treatments (Introduction). The ability to differentiate stem cells into insulin secreting BCs may be a potential method for effective and long-lasting treatment of diabetes (Introduction).
Bose discloses a five-step differentiation protocol (Supp. differentiation conditions). During the third step of differentiation the cells begin to express the gene PDX1 as well as PDX1 protein (Section 3.2, Supp. Figs. S2, S4). PDX1 expression is maintained throughout the remaining differentiation steps (Discussion). Bose discloses that during the fourth step of differentiation the cells begin to demonstrate islet-like morphology and express mature pancreatic genes such as INS (disclosed as insulin) and MafA (Section 3.2, Supp. S2). 24.5% of the cells express the insulin precursor C-peptide, indicating that at this stage in differentiation, the protocol yields 24.5% insulin producing cells (Section 3.2, Supp. S5). The cells also co-express non-β cell pancreatic markers, such as glucagon and somatostatin (Section 3.2, Discussion, Supp. Fig. S2). The fifth step of differentiation results in the formation of compact 3D islet-like clusters (Section 3.1, Fig. 2A, Supp. Fig. S1). The resultant cluster also contains an increase in the yield of insulin producing cells, up to 68.4% (Section 3.2, Fig. 2, Supp. Fig. S6). There is also a significant decrease in the expression of the non-β cell pancreatic markers, glucagon and somatostatin (Section 3.2, Discussion, Supp. Fig. S2). Bose further discloses transplanting the clusters under the left kidney capsule of diabetic mice (Section 2.3).
Regarding claim 25, Bose discloses that the clusters demonstrate a 3-fold increase in insulin secretion following 16.7mM glucose stimulation as compared to baseline insulin secretion (Section 3.3, Fig. 2).
Bose does not explicitly disclose that the cells in the clusters have a diameter of less than 300 µm. However, the figures of Bose indicate that the resultant clusters have a diameter of less than 300 µm (Figs. 1-2, S1). Therefore, it is implicit in Bose that the cells contained in the multi-cell containing cluster would have a diameter of less than 300 µm.
Bose is silent as to 1) expression of chromogranin A, ISL1, ZNT8, MNX1, ABCC8 (claims 24, 30, 32-33, 46), 2) glucose-stimulated calcium flux (claim 29), 3) expression of PC2 (claims 31, 46), 4) expression of MAFB (claims 35, 42), 4) response to a second or third sequential glucose challenge, whether the response is proportional, whether a certain amount of insulin is secreted, or whether the response exhibits a certain stimulation index (claim 36-37, 44), 5) the percent of certain cell populations within the cell cluster (claims 40-41, 50).
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants' non-native pancreatic β cell containing composition is different, and if so to what extent, from the non-native pancreatic β cell containing composition. The prior art discloses a cell cluster comprising non-native pancreatic β cell which is similar to applicant’s non-native pancreatic β cell containing composition for these reasons: the non-native pancreatic β cell contains crystalline insulin granules, expresses c-peptide, PDX1 and MAFA, secretes insulin in response to a glucose challenge, is generated from an embryonic stem cell, and is present in a cell cluster. Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §§102/103 is appropriate. See MPEP §§ 2112-2112.02.
The cited art taken as a whole demonstrates a reasonable probability that the non-native pancreatic β cell of the prior art is either identical or sufficiently similar to the claimed non-native pancreatic β cell containing composition that whatever differences exist, they are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants. See MPEP § 2212(v). Clear evidence that non-native pancreatic β cell of the cited prior art does not possess a critical characteristic that is possessed by the claimed non-native pancreatic β cell would advance prosecution and might permit allowance of claims to applicant’s non-native pancreatic β cell. Applicant is requested to specifically point out the support for any amendments made to the disclosure and arguments in response to this Office Action, including the claims. See MPEP §§ 714.02 and 2163.06. Applicant is also requested to refer to pages and line numbers in the as-filed specification. It is noted that other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Bose does not disclose administering the clusters to a human subject with Type 1 diabetes. However, Bose discloses that the clusters ameliorate diabetes in streptazoicin-induced diabetic mice (Discussion). Bose also suggests that the clusters may be useful for the treatment of Type 1 diabetes (Discussion). Therefore, there is an explicit suggestion present in Bose to try the disclosed clusters for treatment in human subjects.
Regarding claim 28, Bose does not disclose that the stem cells are human induced pluripotent stem cells (iPSCs). However, Bose discloses utilizing human ESCs to generate the cell clusters. A skilled artisan would understand that it would be obvious to try iPSCs in place of ESCs as they are both identified types of pluripotent stem cells, with the predictable result that pancreatic β-like containing cell clusters could be produced.
Claim(s) 38-39, 45, 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bose as applied to claims 24-37, 40-44, 46, 50-51 above, and further in view of Melton et al., US Publication No. 2011/0280842 (cited on IDS dated 9/25/24, hereinafter Melton).
Regarding claim 38, 47, Bose does not disclose administering the composition via the portal vein.
Melton discloses method for the reprogramming of cells of endodermal lineage into pancreatic beta-like cells for the treatment of diabetes (Abstract, [0006]). Melton explains that reprogramming is highly advantageous as it allows for easy harvest of abundant cell types which may be converted to other medically important cell types to repair diseased or damaged tissues, such as for the treatment of diabetes ([0003]-[0004]). Melton discloses that endodermal cells may be transdifferentiated by contacting the cells with an agent which increases protein expression of at least two of the transcription factors Ngn3, Pdx1 and MafA ([0011], [0015]). The resultant mature, pancreatic beta-like cells contain crystalline insulin granules ([0012], [0557], Fig. 3 and 5), express the genes Isl1, Pdx1, C-peptide, MafA ([0008], [0022]-[0024], [0034], [0174], 0198], [0200], [0214], claims 32 and 34), secrete insulin in response to glucose ([0008], [0014], [0041], [0047], [0063], [0198], [0202], [0220], claim 36) and do not express at least one of somatostatin or glucagon ([0203], [0212]). Additionally, the pancreatic beta-like cells can produce and secrete insulin in vivo ([0562]). Melton discloses the cells may also form small clusters in vitro ([0549], Fig. 1C). In some embodiments the pancreatic beta-like cells may be used to treat a human subject that has, or is at risk for developing, Type I diabetes ([0021], [0028]).
Melton does not explicitly disclose that the cells are administered via the portal vein. However, Melton discloses that the pancreatic beta-like cells may be administered by any appropriate route which results in delivery to a desired location in the subject, such as intravenous administration ([0143]-[0144]). Melton also discloses that the cells may be administered directly to the pancreas ([0143]). As Melton discloses both intravenous administration, and administration to the pancreas, it would be obvious to one of ordinary skill in the art to try administration via the portal vein for delivery to the pancreas, with a reasonable expectation of success.
As both Bose and Melton are directed to methods of making cell clusters containing pancreatic beta-like cells which contain crystalline insulin granules, expresses c-peptide, PDX1 and MAFA, secrete insulin in response to a glucose challenge, and do not express somatostatin or glucagon, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to try the transplantation methods of Melton in the methods of Bose for a less invasive transplantation modality, with a reasonable expectation of successful administration.
Regarding claim 39, 45, Bose does not disclose that the pancreatic beta-like cells are genetically modified.
Melton discloses that in some embodiments, the endodermal cell may be genetically modified ([0159], [0164], [0285], [0287], [0290], [0299]). The cells may be modified to enhance survival, control proliferation, or otherwise be modified to introduce genes useful in beta-like cells ([0299]-[0301]). A skilled artisan would be motivated to genetically modify the starting cells of Bose to further enhance survival, control proliferation, or otherwise support the beta-like cells as taught by Melton.
Claim(s) 48, 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bose as applied to claims 24-37, 40-44, 46, 49-51 above, and further in view of Yang et al., (2002) Survival of pancreatic islet xenografts in NOD mice with the theracyte device. Transplantation Proceedings, 34(8), 3349-3350 (cited on IDS dated 9/25/24, hereinafter Yang).
Regarding claims 48, 52 30, Bose does not disclose that the composition is contained within an implantable device.
Yang discloses methods of reducing rejection of transplanted cells using encapsulation to separate engrafted cells from host cells (Abstract). Yang explains that encapsulation devices allow for microcirculation around the device, and are permeable to insulin and glucose(Introduction, Discussion). Yang discloses transferring pancreatic islets into a TheraCyte device (TheraCyte, Irvine, CA) and implanting subcutaneously (Materials and Methods). Use of the device allows for prolonged islet survival and supports reversal or hyperglycemia (Discussion).
As Bose, and Yang are both directed to methods of treating diabetes, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to encapsulate the composition of Bose in the device of Yang to improve cell survival for transplantation.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
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, Peter Paras can be reached at (571) 272-4517. 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.
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
Prosecution Insights