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 .
Applicant’s amendments and arguments of June 30, 2026, are entered.
Claims 1, 3-4, 6-10, 13-15, 17, 19, 21, 23, 25-27, 32-33, and 35-38 have been amended.
Claims 18, 22, 24, and 28 have been canceled.
No new claims have been added.
Examiner’s Note
Claims 19, 25, and 29 have not been considered because the claims improperly depend from canceled claims. However, to maintain compact prosecution, claims 19, 25, and 29 been in proper dependent form, the rejections based on the previously cited prior art as stated in the Non-Final Office Action would have been maintained.
Claim Objections
In light of Applicant’s amendments, the objection to claim 26 is withdrawn.
Claim Rejections - 35 USC § 112
In light of Applicant’ canceling claim 22, the rejection for failing to comply with the enablement requirement is withdrawn.
Claim Rejections - 35 USC § 112
In light of Applicant’s amendments and canceling claim 22, the rejection for lack of written description for claims 1, 22, 23, and 27 are withdrawn.
Claim Rejections - 35 USC § 112
In light of Applicant’s amendments, the rejection for claims 4, 10, 22, 26, 32, and 35-36 as being indefinite is withdrawn.
Claim Rejections - 35 USC § 102
In light of Applicant’s amendment to claim 26, the §102 rejection for claim 26 is withdrawn.
Claim Rejections - 35 USC § 103
In light of Applicant’s amendments, the §103 rejection for claims 27 and 30-38 is withdrawn.
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, 25, and 29 are newly 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.
Claim 19 depends from claim 18. Claim 18 has been canceled, and therefore, claim 19 is indefinite.
Claim 25 depends from claim 24. Claim 24 has been canceled, and therefore, claim 25 is indefinite.
Claim 29 depends from claim 28. Claim 28 has been canceled, and therefore, claim 29 is indefinite.
Claim Rejections - 35 USC § 102
Claims 1, 2, 5, 6, 20, 21, and 23-24 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Chang et al. [Induced pluripotent stem cell-derived enteric neural crest cells repopulate human aganglionic tissue-engineered intestine to from key components of the enteric nervous system, J Tissue Eng., 2020] is being maintained.
Regarding claim 1, Chang et al. teaches a method to treat an enteric neuropathy [Abstract] comprising administering enteric neural crest cells (ENCCs) to a muscular wall of the intestine in a subject in need thereof [Figure 1 & Figure 2], wherein the ENCCs are differentiated from stem cells [Abstract].
Regarding claim 2, Chang et al. teaches the method of claim 1, wherein the enteric neuropathy is Hirschsprung’s Disease (HD) [Introduction ¶ 1].
Regarding claim 5, Chang et al. teaches the method of claim 1, wherein the entire intestine is aganglionic [Abstract].
Regarding claim 6, Chang et al. teaches the method of claim 1, wherein the cells are administered by injection [Figure 1].
Regarding claim 20, Chang et al. teaches the method of claim 1, wherein the cells are allogeneic to said subject [HIO and ENCC generation ¶ 1].
Regarding claim 21, Chang et al. teaches the method of claim 1, wherein the cells are genetically modified [HIO and ENCC generation ¶ 1].
Regarding claim 23, Chang et al. teaches enteric neural crest cells differentiated from stem cells in vitro and a cryopreservative [HIO and ENCC generation ¶ 1. Furthermore, LiPSC-GR1.1 is shipped frozen where it is typically cryopreserved in a protective solution such as DMSO].
Regarding claim 24, Chang et al. teaches wherein the stem cells comprise induced pluripotent stem cells or embryonic stem cells [HIO and ENCC generation ¶ 1].
Response to Argument
Applicant argues that Chang et al. generally discusses models for enteric neuropathies, in which intestinal nerves are absent or injured, to evaluate possible cell therapies as stated in the abstract. Applicant further argues that the instant claims are directed towards a method for treating enteric neuropathies, compositions for treating enteric neuropathies, and methods for producing ENCCs for treating enteric neuropathies.
Examiner appreciates Applicant’s argument. However, the examiner does not Applicant’s argument persuasive. To start, Applicant argues that Chang et al. is directed merely to animal models for evaluating potential cell therapies versus treating enteric neuropathies. Chang et al. expressly discloses an in vivo model in which induced pluripotent stem cell derived enteric neural crest cells are administered to tissue-engineered small intestine, i.e. TESI, that is developed in immunocompromised mice in order to model aganglionic intestinal tissue and enteric neuropathy. Specifically, in the “HIO and ENCC generation” section, Cheng et al. generates enteric neural crest cells from an induced pluripotent stem cell line uising an invitor differentiation protocol. In the “Surgical procedures” section, HIOs are implanted into mice and allowed to develop into TESI for 10 weeks. During a subsequent survival surgery, only mice in which TESI growth was identified were retained for the study. These mice then had the derived enteric neural crest cells injected into the TESI. Chang et al. further reported that the administered ENCCs gave rise to neuronal and glial cells that included ganglion-like structures located with the muscle layer of the TESI. Chang et al. further stated that sequential models were developed to approximate the clinical scenario encountered in patients with enteric neuropathies and evaluated cell therapies for such conditions, i.e. the authors were contemplating treating “subjects in need thereof”. Therefore, Cheng et al. discloses administration of induced pluripotent stem cell-derived enteric neural crest cells in vivo to an intestinal tissue construct exhibiting the pathological features of an enteric neuropathy where the administration occurred to TESI that had a muscle layer. The fact that Cheng et al. characterizes the system as an animal model and as a means for evaluating cell therapy does not distinguish from Applicant’s claimed method where the reference discloses the same cells, the same in vitro differentiation, the same in vivo administration, and the same enteric neuropathy context. Based on this, the §102 rejection for claims 1, 2, 5, 6, 19, 20, 21, and 23-25 is being maintained.
Claim Rejections - 35 USC § 103
The rejection for claims 3-4, 7-17 under 35 U.S.C. §103 is being maintained and Claims 26-27 and 30-38 are newly rejected under 35 U.S.C. §103 as being unpatentable over Chang et al. [Induced pluripotent stem cell-derived enteric neural crest cells repopulate human aganglionic tissue-engineered intestine to from key components of the enteric nervous system, J Tissue Eng., 2020], in view of Moore [Hirschsprung Disease: current perspectives, Taylor & Francis Group, 2015], in view of Meneghel et al. [Cryopreservation as a key element in the successful delivery of cell-based therapies – a review, Front. Med., 2020], in view of McKeown et al. [Exposure to GDNF enhances the ability of enteric neural progenitors to generate an enteric nervous system, Stem Cell Reports, 2017], in view of Fattahi et al. [Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease, Nature, 2016], in view of Menendez et al. [Wnt signaling and a SMAD pathway blockage direct the differentiation of human pluripotent stem cells to multipotent neural crest cells, Cell Biology, 2011], in view of Allison [Immunosuppressive therapy in transplantation, Nursing Clinics of North America, 2016], in view of Lee et al. [Divergent effects of Wnt/Beta-catenin signaling modifiers on the preservation of human limbal epithelial progenitors according to culture condition, Nature: Scientific Reports, 2017], in view of Huang et al. [Characterization and transplantation of enteric neural crest cells from human induced pluripotent stem cells, Nature: Molecular Psychiatry, 2016].
Chang et al. teaches each and every element for claims 1 and 2. However, Chang et al. does not specifically cite total intestinal agangliosis form of HD or a long segment form of HD as stated in claim 3. However, Moore, discussing the known characteristics of Hirschsprung disease, discloses long segment agangliosis being associated with HD, as well as ultra-long segment aganglionosis, also known as Zuelzer’s disease [Familial transmission ¶ 2]. This disclosure coupled with the disclosure in Chang et al. where the abstract mentions the absence of intestinal nerves, it would have prima facie obvious to a person of ordinary skill prior to the filing of the claimed invention to modify the systems and methods of Chang et al. that discloses using enteric neural crest cells derived from pluripotent stem cells for treating enteric neuropathy, e.g. HD, where the treatment focused on total agangliosis or long-segment agangliosis. Given this, there is a reasonable expectation of success that an artisan would recognize the teachings of both Chang et al. and Moore where enteric neural crest cells derived from pluripotent cells, natural or induced, could be differentiated into enteric neural crest cells for the treatment of total or long-segment agangliosis resulting from HD.
For claim 4 where the method of claim 1 is used to treat enteric neuropathy chosen from a Markush listing, Moore teaches that Hirschsprung disease, although varies considerably, is known to classically affect the rectum and sigmoid where the aganglionosis extends proximally for short and long segments depending on phenotypic expression [Pathology ¶ 2].
For claim 7 where the cells are administered to two or more locations, Although Chang et al. discloses the method of administering enteric neural crest cells by injection, Chang et al. does not specifically disclose method of administering enteric neural crest cells to two or more locations of the intestine. However, administering stem cells or enteric neural crest cells to two or more locations along the intestine would have been a matter of routine optimization using known methods, given a person of ordinary skill in the art would recognize that the intestine is an elongated organ and that multiple-site injection administration would be necessary in order to improve cell distribution, engraftment, and homing of the enteric neural crest cells.
Additionally, for claims 8, 9, and 10 where the administration of the cells involve bilateral injections every 1 to 3 centimeters, a person of ordinary skill would also understand that in order to maximize efficacy and homing of the enteric neural crest cells, given the elongated nature of the intestines, that multiple injections would be required for each section of the intestine in order for the neural crest cell base to cover the intestinal wall based where the number of injections would be determined in the amount of agangliosis present in the subject. This would depend further whether the area affected was due to total agangliosis, short-form agangliosis, long-form agangliosis, or even ultra long-form agangliosis, a person of ordinary skill would recognize that in order for the administration of enteric neural crest cells needed to cover the entire affected area of the intestine would require both multiple injections along the length of the intestine at predetermined lengths, as wells as bilateral injections for treating the entire circumference of the intestine. Additionally, targeting the muscular wall of the intestine would also be obvious to a person of ordinary skill given that restoring neurons in the myenteric plexus region would be critical for restoring peristalsis and/or coordinated muscle contraction. Additionally, Chang et al. discloses multiple injection sites shown as scaffold seeding in part (a) in Figure 1.
For claim 11 and claim 12 where the method of claim 8 is made up of a dose comprising a particular cellular concentration, Chang et al. discloses the concentration of 1 x 105 cells [Surgical procedures ¶ 1]. However, cell concentration selection also represents a matter of routine optimization using known methods. A person of ordinary skill in the art would know to adjust cell density or dose to achieve a therapeutic benefit based on considerations such as target tissue, delivery method, and treatment efficacy.
For claim 13, Chang et al. discloses pluripotent stem cell-derived enteric neural crest cells were introduced into an engineered small intestine implant as a cell suspension. Additionally, the cell suspension included an acceptable carrier where the cells were prepared in a liquid injection medium [Figure 1].
For claim 14 where the cells are cryopreserved, Meneghel et al., discloses that cryopreservation is a key enabling technology for use in regenerative medicine allowing for secure extended cell storage of prepared cell preparations [Abstract].
For claim 15 where additional agents, such as pH buffering agent, is administered, McKeown et al., discussing GDNF and its role in generating an enteric nervous system, discloses that GDNF resulted in a 14-fold increase in nuerosphere volume and a 12-fold increase in cell number following co-culture with embryonic gut or transplantation into the colon of postnatal mice. Additionally, cells derived from GDNF-treated neurospheres showed a 2-fold increase in the distance migrated compared with controls [Abstract]. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would recognize the benefits of utilizing GDNF as a migration agent given its ability increase migration in enteric neural progenitor cells. Therefore, it is prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Chang et al. with the additional teachings of McKeown et al. where a person of ordinary skill would recognize the benefits of utilizing GDNF as a migration agent in order to better facilitate homing of the enteric neural crest cells in allowing these cells to migrate and develop into an enteric nervous system as it relates to Hirschsprung disease.
For claim for claim 16 where the migration promotion agent includes GDNF, again McKeown discloses the use of GDNF as a plausible migration agent given its success in increases both volume and migration distance with enteric neuronal progenitor cells [Abstract].
For claim 17 where the subject has been clinically immunosuppressed prior to administration, Allison, discussing immunosuppressive therapy in transplantation, discloses that immunosuppressive medications are given in order to modulate the recipients immune response to the donor organ, tissue, and/or cells [Key Points]. This involves both induction, e.g. prior to surgery, and maintenance therapy [Key Points].
For claim 26, Huang et al. teaches a neurosphere [hiPSC-NCSCs can colonize aganglionic human gut tissue in vitro ¶ 1] comprising a heterogenous mixture of cells, wherein the mixture of cells are positive for expression of HNK-1, positive for expression p75, negative for expression of Oct4 and negative for expression Nanog, wherein the expression of HNK-1, p75, Oct 4 and/or Nanog is from one cell or each marker is expressed individually or in combination on different cells [Derivation of enteric-like neurons from hiPSC-NCSCs in vitro ¶ 1]. However, Huang et al. does not teach the presence of certain cell markers such as PCNA. For this limitation, Cheng et al. teaches “that despite the fact that D15 ENCCs demonstrate proliferative capacity with a high level of PCNA expression, pluripotency marker OCT4 is completely absent” [Results]. Based on this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Huang et al. that discloses transplantation of enteric neural crest cells that are derived from human induced pluripotent stem cells with the teachings of Cheng et al. that also is directed to producing enteric neural crest cells derived from induced pluripotent stem cells where Cheng et al. further explained that the ENCCs showed a high expression rate of PCNA with a complete absence of OCT4. Therefore, there would have been a reasonable expectation of success for a person of ordinary skill in the art to combine the teachings of both Huang et al. coupled with Cheng et al. in order to analyze enteric neural crest cells derived from induced pluripotent stem cells for specific cell markers to confirm the presence of enteric neural crest cells prior to administration.
For claim 27 where a method of producing enteric neural crest cells contains a number of steps, Fattahi et al., discussing methods for culturing and deriving human enteric nervous system cell lineages, including neural crest cells, discloses expanding the cells in suspension [In vitro differentiation of ENC to enteric neurons ¶ 1] contacting the stem cells with FGF2 and retinoic acid [Neural crest induction ¶ 1, Main ¶ 1], and further isolating the resultant cell lines [Abstract]. However, Fattahi et al. is silent on the use of an inhibitor of SMAD and a WNT pathway activator. For the SMAD and WNT signaling, Menendez et al., discussing ways to differentiate human pluripotent stem cells into neural crest cells, discloses that concurrent SMAD inhibition combined with activation of WNT signaling markedly increased p75 cells, a known cellular marker for neural crest cells [Results: Activation of the Wnt Pathway Redirects Neural Progenitors toward a Neural Crest Fate ¶ 1]. However, neither Fattahi et al. nor Menendez et al. teach verifying the presence of certain cell markers in order to confirm the presence of enteric neural crest cells that were derived from induced pluripotent stem cells. For this limitation Cheng et al. teaches “that despite the fact that D15 ENCCs demonstrate proliferative capacity with a high level of PCNA expression, pluripotency marker OCT4 is completely absent” [Results]. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of both Fattahi et al. and Menendez et al. with the further teachings of Cheng et al. that disclosed the confirmation of certain cell markers being present in order to identify the presence of enteric neural crest cells that were derived from induced pluripotent stem cells.
For claim 30 where the inhibitor can be SB431542, Menendez et al. discloses the use of SM431542 as an inhibitor capable of blocking SMAD [Results: Activation of the Wnt Pathway redirects neural progenitors towards a neural crest fate ¶ 3].
For claim 31 where the WNT activator is CHIR99021, Lee et al., discussing WNT signaling modifiers, discloses that CHIR99021 is a known as a primary inducer of the WNT signaling canonical pathway [Abstract].
For claim 32, the same analysis for claim 27 applies.
For claim 33 where the where the isolated enteric neural crest cells are cryopreserved prior to administration, the same analysis for claim 14 applies.
For claim 34, the same analysis for claim 27 applies.
For claim 35 where the enteric neural crest cell culture is substantially homogenous, Huang et al. discloses using FACS to isolate p75 and HNK-1 dual positive cells where these cells represented approximately 90% among the differentiated HDF-hiPSCs [Generation of NCSCs from hiPSCs ¶ 2].
For claim 36 where the enteric neural crest cells comprise a heterogenous cell population, Huang et al., similar to the above statement, discloses a heterologous cell population that contains dual positive p75 and HNK-1 cells among other cell types [Id.].
For claim 37 where a pharmaceutical composition containing enteric neural crest cells, the same analysis for claim 13 is applicable.
For claim 38 containing a method for treating an enteric neuropathy by injecting the enteric neural crest cells to a muscular wall of the intestine to a subject in need thereof, the same analysis for claim 1 coupled with the analysis for claim 34 is applicable.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument
Please see response to argument for claim 1 and why claim 1 being rejected for being anticipated under 35 U.S.C. §102(a)(1) as being maintained. This same rational is applied to claims 3-4 and 7-17.
Additionally, claims 26 and 27 are newly rejected, as stated above, in view of Cheng et al. where Cheng et al. teaches the presence of cell markers, e.g. PCNA, are present in enteric neural crest cells. Therefore, claims 26 and 27, and all dependent claims, are newly rejected under 35 U.S.C. §103.
Conclusion
No claims allowed.
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 JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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