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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/15/2026 has been entered.
Status of the Claims
This action is in response to papers filed 05/15/2026 in which claims 2-3 were canceled; and claims 6-8 were withdrawn; claim 1 was amended; and claim 9 was newly added. All the amendments have been thoroughly reviewed and entered.
Claims 1, 4, 5, and 9 are under examination.
New Rejection
Necessitated by Applicant’s Claim Amendments
Claim Rejections - 35 USC § 112 – NEW MATTER
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4 and 5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 introduces new matter as the claims recite the limitation: ”0.05 w/v% to 0.07 w/v% poly-L-ornithine solution.” There is no support in the specification for the maximum point of “0.07 w/v%” poly-L-ornithine solution.
Applicant asserted that support for the amendments can be found throughout the specification, including for example, at paragraphs [0026], [0032], [0033], and [0044], and the Examples (see Remarks filed 05/15/2026, page 4).
However, after a thorough review of paragraphs [0026], [0032], [0033], and [0044], and the Examples, as well as, throughout the specification, there remained no support for the maximum point of “0.07 w/v%” poly-L-ornithine solution.
It is noted that paragraph [0026] of the specification discloses that the concentration of the poly-L-orthinine in the poly-L-ornithine solution A is preferably 0.05 w/v% or more to less than 1 w/v, or the poly-L-ornithine solution A is preferably 0.9 w/v% or less or 0.8 w/v% or less. While formulation 1 of the five-layered membrane in the Example under paragraph [0044] discloses the use of 0.075 w/v% PLO for the poly-L-ornithine solution A, this concentration is different from the claimed maximum point of “0.07 w/v%” for poly-L-ornithine solution. While applicant has support for the maximum point of 0.075 w/v% for the concentration of poly-L-ornithine, Applicant does not have support and possession of maximum point of “0.07 w/v%” for poly-L-ornithine solution as claimed.
Claims 4 and 5 are also rejected as they depend directly or indirectly from claim 1, thereby also containing the new matter material.
As such, the disclosure does not reasonably convey that the inventor had possession of the subject matter of amended claim 1 at the time of filing of the instant application.
Claim Interpretation
Claims 1 and 9 are structured as a product-by-process with regards to the limitations “the second membrane from the inner side is formed using a 0.05 w/v% to 0.07 w/v% poly-L-ornithine solution followed by a 0.01 w/v% to 0.038 w/v% poly-L-ornithine solution and the fourth membrane from the inner side is formed using a 0.01 w/v% to 0.038 w/v% poly-L- ornithine solution” and “the second membrane from the inner side is formed using a 0.075 w/v% poly-L-ornithine solution followed by a 0.038 w/v% poly-L-ornithine solution and the fourth membrane from the inner side is formed using a 0.038 w/v% poly-L-ornithine solution,” respectively. Thus, claims 1 and 9 will be interpreted and examined for art rejection purposes (103 rejection) as product-by-process type claim. MPEP §2113 (I) states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Thus, while the structure implied by the process steps should be consider when assessing patentability of product-by-process claims over the prior art; however, burden of proof is placed upon Applicant to show that the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). Also see MPEP § 2113.
Modified Rejection
Necessitated by Applicant’s Claim Amendments
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) 1, 4-5, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hillberg et al (Journal of Biomedical Materials Research B: Applied Biomaterial, February 2013, 101B(2): 258-268) in view of Agarwal et al (US 2015/0283287 A1) and Anderson et al (US 2019/0254975 A1).
The Claim Interpretation applies here.
Regarding claims 1 and 9, Hillberg teaches a capsule having a core containing pancreatic islet, wherein the core is an alginate bead containing pancreatic islet, wherein the alginate bead is coated with a layer of polyornithine, and followed by another layer of alginate (Abstract; Introduction; pages 259-260).
While Hillberg does not expressly teach that the capsule is a five-layered membrane, it would have been obvious to prepare the capsule of Hillberg to contain additional bilayer coating of polyornithine/alginate around the outermost layer of alginate in view of the guidance from Agarwal.
Agarwal teaches the encapsulation of cells such as pancreatic cells by a multilayer polymer matrix formed by alternating layers of at least one positively charge polyelectrolyte and at least one negatively charge polyelectrolyte, wherein the positively charged polyelectrolyte includes poly(ornithine) and the negatively charge polyelectrolyte include an alginate (Abstract; [0013], [0018], [0058]-[0059], [0140], [0165], [0193], [0201], [0204], [0293], [0296], and [0302]). Agarwal teaches the multilayer polymer matrix can be designed to have at least 4 alternating layers ([0193]). Agarwal teaches the multilayer polymer matrix have excellent mechanical strength ([0106] and [0319]).
It would have been obvious to one of ordinary skill in the art to modify the to modify the capsule of Hillberg to contain additional bilayer coating of polyornithine/alginate around the outermost layer of alginate, and produce the claimed five-layered membrane that cover the core containing pancreatic islet. One of ordinary skill in the art would have been motivated to do so because Agarwal provide the guidance to do so by teaching that the encapsulation of pancreatic cells can tailor to have at least 4 alternating layers of positively charged polyelectrolyte such as polyornithine and negatively charged polyelectrolyte such as alginate, and such resultant multilayer polymer matrix have excellent mechanical strength. One of ordinary skill in the art would have reasonable expectation of success in making said modification to Hillberg because one of the objective of Hillberg is to provide polymeric capsules having excellent mechanical properties (Hillberg: Abstract & Introduction), as well as, Figure 3 in Hillberg contemplate and suggest the production of capsule having 2 alternating sets of polyornithine and alginate and an outer layer of alginate (Hillberg, page 262). As such, an ordinary artisan would have looked to modifying the capsule of Hillberg to contain additional bilayer coating of polyornithine/alginate around the outermost layer of alginate so as achieve a desired multilayer capsule with enhanced mechanical strength, and achieve Applicant’s claimed invention with reasonable expectation of success.
However, Hillberg and Agarwal do not teach the formulation has an average diameter of 400 µm or more to 500 µm or less of claims 1 and 9.
Regarding the formulation has an average diameter of 400 µm or more to 500 µm or less of claims 1 and 9, Anderson teaches encapsulation of pancreas cells such as pancreatic islet using alternating layers of anionic polymer such as alginate and polycationic polymer such as polyornithine (Abstract; [0013]-[0105]). Anderson teaches the encapsulation is in microcapsules having mean diameter of 300 µm to about 750 µm, preferably, about 200 μm to about 500 μm, most preferably from about 400 µm to about 500 µm ([0018], [0098]; claim 5).
It would have been obvious to one of ordinary skill in the art to optimize the capsule of Hillberg in view of Agarwal to an average diameter of 400 µm or more to 500 µm or less, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Anderson provided the guidance to do by teaching that capsules for encapsulation of pancreatic cells can be routinely fabricated to have mean diameter of 300 µm to about 750 µm, and most preferably from about 400 µm to about 500 µm, and such mean diameter is suitable for administration to a patient in the treatment of diabetes. It is noted that Hillberg is also using the encapsulated pancreatic islet for the treatment of diabetes (Hillberg: Abstract; Introduction; pages 259-260). Thus, an ordinary artisan would have looked optimizing the capsule of Hillberg in view of Agarwal to mean diameter of from about 400 µm to about 500 µm, a particle size that is suitable for use in the treatment of diabetes, and achieve Applicant’s claimed invention with reasonable expectation of success.
With respect to the claimed concentrations as recited in claims 1 and 9, as discussed in the Claim Interpretation section, the limitations “the second membrane from the inner side is formed using a 0.05 w/v% to 0.07 w/v% poly-L-ornithine solution followed by a 0.01 w/v% to 0.038 w/v% poly-L-ornithine solution and the fourth membrane from the inner side is formed using a 0.01 w/v% to 0.038 w/v% poly-L- ornithine solution” and “the second membrane from the inner side is formed using a 0.075 w/v% poly-L-ornithine solution followed by a 0.038 w/v% poly-L-ornithine solution and the fourth membrane from the inner side is formed using a 0.038 w/v% poly-L-ornithine solution,” as recited in claims 1 and 9 respectively, is structured as a product by process and thus, how the second membrane and the fourth membrane of the formulation is formed using the concentrations of poly-L-ornithine solution, is immaterial to the patentability of the product, as the patentability of a product does not depend on its method of production. Hillberg provided the process of preparing the capsule and the alternating layers of poly-L-ornithine and alginate (Hillberg: page 259 and Figure 3) and thus, it is routine for a skilled artisan to repeat the steps of forming the alternating layers of poly-L-ornithine and alginate, as well as, optimize the concentration of the poly-L-ornithine solution used to achieve a desired multilayer capsule (e.g., 5-layered membrane with 2 sets of alternating layers of poly-L-ornithine and alginate) with enhanced mechanical strength as suggested and desired by Hillberg and Agarwal, and ultimately a resultant multilayer capsule for encapsulation of pancreatic cells having a desired diameter size (e.g., 300 µm to about 750 µm ) so as the capsule is suitable for administration to a patient in the treatment of diabetes per Hillberg and Anderson. Thus, it is also noted that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 (I)-(II). As such, while the structure implied by the process steps should be consider when assessing patentability of product-by-process claims over the prior art; however, burden of proof is placed upon Applicant to show that the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). Also see MPEP § 2113.
Regarding claim 4, Hillberg teaches the encapsulated pancreatic islet is used for the treatment of diabetes (Abstract; Introduction; page 259).
Regarding claim 5, Hillberg teaches the pancreatic islet was obtained from seven to 10 day old neonatal piglets (page 259, bottom of left column to top of right column).
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 before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 05/15/2026 in have been fully considered but they are not persuasive.
Applicant argues:
“The specification exemplifies three five-layered membrane formulations and shows that all of them inhibited an increase in blood glucose level when administered into diabetic mice for a long period of time, as compared to administration of a three-layered membrane formulation. See, Specification, paragraphs [0044]-[0046] and [0050], and Fig. 1. Among the three exemplified five-layered membrane formulations, only five-layered membrane formulation 1 produced capsules having a mean particle size within the claimed range (i.e., 400 pm or more to 500 pm or less) and was shown to significantly inhibit fibrosis. See, id., paragraph [0051] and Fig. 2. This formulation produced capsules using a 0.075% (wt/vol) poly-L-ornithine solution followed by a 0.038% (wt/vol) poly-L-ornithine solution to form the first layer of polyornithine-containing membrane, and a 0.038% (wt/vol) poly-L-ornithine solution to form the second layer of polyornithine-containing.
Applicant notes that the three-layered membrane formulation disclosed in the present application as a comparison also produced capsules having a mean particle size within the claimed range and significantly inhibited fibrosis, similar to five-layered membrane formulation 1. See, id., Fig. 2. This three-layered membrane formulation uses a 0.075% (wt/vol) poly-L-ornithine solution followed by a 0.038% (wt/vol) poly-L-ornithine solution to form the layer of membrane containing polyornithine. See, id., paragraph [0043].
Applicant notes that the concentration of poly-L-ornithine in the solution used in Hillberg to form the poly-L-ornithine coating (i.e., 0.1% (wt/vol) followed by 0.05% (wt/vol)) is the same as that used in forming the first layer of polyornithine-containing membrane in five-layered membrane formulation 2 disclosed in the present application. See, Specification, paragraph [0045]. As shown in Fig. 2, this formulation also did not produce capsules having a mean particle size within the claimed range and did not inhibit fibrosis.
The third five-layered membrane formulation disclosed in the present application, i.e., five- layered membrane formulation 3, uses a 0.15% (wt/vol) poly-L-ornithine solution followed by a 0.075% (wt/vol) poly-L-ornithine solution to form the first layer of polyornithine-containing membrane, and a 0.038% (wt/vol) poly-L-ornithine solution to form the second layer of polyornithine-containing membrane. See, id., paragraph [0046]. This formulation also did not produce capsules having a mean particle size within the claimed range and did not inhibit fibrosis. See, id., Fig. 2.
These results indicate that the concentration of poly-L-ornithine in the solution used to form each layer of polyornithine-containing membrane can be important in producing capsules with a mean particle size that contributes to fibrosis inhibition. None of the cited art teaches or suggests how to achieve a five-layered membrane formulation that can produce capsules having a mean particle size within the claimed range.
Following the Office's rationale, one of ordinary skill in the art would have only used a 0.1% (wt/vol) poly-L-ornithine solution followed by a 0.05% (wt/vol) poly-L-ornithine solution to form the first layers of polyornithine-containing membrane, and perhaps also the second layers of polyornithine-containing membrane, as taught in Hillberg, which would not produce capsules having a mean particle size within the claimed range, as demonstrated by five-layered membrane formulation 2 disclosed in the present application. While Anderson discloses that a mean particle size of 400 pm to 500 pm is preferred for microcapsules, none of the cited art teaches or suggests how to achieve this goal.” (Remarks, pages 5-7).
In response, the Examiner disagrees. Applicant’s arguments and unexpected results as shown in the specification are considered, but found insufficient to obviate the pending 103 rejection over the combined teachings of Hillberg, Agarwal, and Anderson for the reasons set forth below.
While Applicant had shown in Fig. 1 that the five-layered membrane formulation 1 provided enhanced results in inhibiting an increase in blood glucose level when administered into diabetic mice for a long period of time, claim 1 is not adequately commensurate in scope with the particular five-layered membrane formulation 1. Thus, claim 1 remained broad to encompass a formulation in which there is no predictability if a formulation using 0.05 w/v% poly-L-ornitine solution followed by a 0.01 w/v% poly-L-ornitine solution to form the second membrane and 0.01 w/v% poly-L-ornitine solution to form the fourth membrane, which is a formulation encompassed by claim 1, would provide enhanced results to the same extent as shown in Fig. 1. See MPEP §716.02 (d).
While claim 9 is commensurate in scope with five-layered membrane formulation 1, Applicant’s correlation of the concentration of poly-L-ornithine in the solution used to form each layer of polyornithine-containing membrane of the five-layered membrane formulation 1 to achieve the mean particle size that contributes to fibrosis inhibition as shown in Fig. 2, is not persuasive, as it was shown in Fig. 2, the three-layered membrane formulation had a mean particle size with the claimed “average diameter of 400 µm or more to 500 µm or less” and this three-layered membrane formulation had better fibrosis inhibition than the five-layered membrane formulation 1. Furthermore, is it noted that while the capsules of Hillberg have diameters of about 700 µm, the capsule were shown to also inhibit fibrosis (Hillberg, pages 264-267 and Tables II and III and Figure 5). Furthermore, as previously discussed of record, the longer activity shown in Fig. 1 of suppressing blood glucose levels for a period of more than 60 days appeared not unexpected or surprising, but rather obvious because the three-layered membrane capsule of Hillberg already provided prolonged release of the pancreatic islet for 30 days and thus, adding additional bilayers per Agarwal would obviously extend the activity longer than 30 days. Thus, Applicant has not shown criticality of the claimed concentrations of poly-L-ornithine in forming the poly-L-ornithine membranes of the five-layered membrane in achieving a result that was unexpected when compared to the closest prior art of Hillberg because as discussed above, the three-layered membrane formulation shown in the specification had a mean particle size with the claimed “average diameter of 400 µm or more to 500 µm or less” and this three-layered membrane formulation had better fibrosis inhibition than the five-layered membrane formulation 1. As such, it is noted that MPEP 716.02(e) states “[a]n affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
Applicant argues:
“Applicant notes that Hillberg discloses use of genipin crosslinking to improve alginate-poly-L-ornithine-alginate capsule biocompatibility in order to address the risk of fibrosis. See e.g., Hillberg, Abstract. In contrast, the present application shows that, when the capsules have a mean particle size within the claimed range, i.e., 400 µm or more to 500 µm or less, fibrosis was significantly inhibited. See, Specification, paragraph [0051] and Fig. 2. None of the cited art teaches or suggests that reducing the mean particle size of the capsules could lead to fibrosis inhibition. Accordingly, in searching for ways to inhibit fibrosis, one of ordinary skill in the art would not have been motivated to look to the contribution of mean particle size of the capsules in fibrosis and would not have been motivated to reduce the mean particle size of the capsules with a reasonable expectation that fibrosis would be inhibited.” (Remarks, page 7, 2nd paragraph).
In response, the Examiner disagrees. As discussed above, Applicant’s correlation of the concentration of poly-L-ornithine in the solution used to form each layer of polyornithine-containing membrane of the five-layered membrane formulation 1 to achieve the mean particle size that contributes to fibrosis inhibition as shown in Fig. 2, is not persuasive, as it was shown in Fig. 2, the three-layered membrane formulation had a mean particle size with the claimed “average diameter of 400 µm or more to 500 µm or less” and this three-layered membrane formulation had better fibrosis inhibition than the five-layered membrane formulation 1. Furthermore, is it noted that while the capsules of Hillberg have diameters of about 700 µm, the capsule were shown to also inhibit fibrosis (Hillberg, pages 264-267 and Tables II and III and Figure 5). Furthermore, as previously discussed of record, the longer activity shown in Fig. 1 of suppressing blood glucose levels for a period of more than 60 days appeared not unexpected or surprising, but rather obvious because the three-layered membrane capsule of Hillberg already provided prolonged release of the pancreatic islet for 30 days and thus, adding additional bilayers per Agarwal would obviously extend the activity longer than 30 days. Thus, Applicant has not shown criticality of the claimed concentrations of poly-L-ornithine in forming the poly-L-ornithine membranes of the five-layered membrane in achieving a result that was unexpected when compared to the closest prior art of Hillberg because as discussed above, the three-layered membrane formulation shown in the specification had a mean particle size with the claimed “average diameter of 400 µm or more to 500 µm or less” and this three-layered membrane formulation had better fibrosis inhibition than the five-layered membrane formulation 1. As such, it is noted that MPEP 716.02(e) states “[a]n affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
As a result, for at least the reasons discussed above, claims 1, 4, 5, and 9 remain rejected as being obvious and unpatentable over the combined teachings of Hillberg, Agarwal, and Anderson in the standing 103 rejection as set forth in this office action.
Conclusion
No claim is allowed.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613
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