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 .
Status of the Claims
Claims 3, 6-8, 11, 16, 20-22, 26-27, 29-30, 32-35, 39-40, 43-44, and 47-49 are cancelled. Claims 1-2, 4-5, 9-10, 12-15, 17-19, 23-25, 28, 31, 36-38, 41-42, and 45-46 are pending. Claim 46 is withdrawn. Claims 1-2, 4-5, 9-10, 12-15, 17-19, 23-25, 28, 31, 36-38, 41-42, and 45 are under examination.
Priority
This application is a national stage entry of PCT/US2022/013943 filed on 1/26/2022, which claims priority from 63/141,892 filed on 1/26/2021.
Information Disclosure Statement
The information disclosure statement filed on 07/25/2023 has been considered by the examiner.
Election/Restriction
Applicant’s election without traverse of Group I and species A, C, D and E (claims 1, 2, 4, 5, 9, 10, 12-15, 17-19, 23-25, 28, 31, 36-38, 41, 42, and 45) in the reply filed on 5/4/2026 is acknowledged. Species were elected as A) hydrogel capsule, C) ARPE-19 cells, D) soluble CTLA-4 protein, soluble FLT3 protein and rapamycin, E) compound 101 of the specification.
Claim 46 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/4/2026.
Claim Objections
Claim 2 is objected to for “(vii) the first plurality or genetically modified”, which should be “(vii) the first plurality of genetically modified”.
Claim 12 is object to for using “and” in the claim with “selected from” where the recitation should be “selected from….or…”.
Appropriate corrections are required.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 1-2, 4-5, 9-10, 12-15, 17-19, 23, 37-38, 41, and 45 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. Claims 1 and 37 provide for items defined in functional terms (a) continuously deliver each secreted at least one immunomodulatory protein and at least one immunosuppressant compound are delivered in an amount and for a time period effective to induce immune tolerance in the subject, (b) prevent the subject’s immune cells from contacting the genetically modified mammalian cells, (c) prevent the genetically modified mammalian cells from exiting the device, and (d) mitigate the foreign body response to the implanted device. Applicant’s description provides particular structures as part of hydrogel capsules to accomplish each of these functions. Part (a) is accomplished with the immunosuppressant compound being part of an extended release formulation, parts (b) and (c) accomplished with a cell containing compartment that comprises living cells encapsulated in a first polymer composition and a barrier compartment surrounding the cell-containing compartment and comprising a second polymer composition and part (d) is accomplished with the alginate covalently modified with groups as in part (c) of claim 24 and/or with a formulation of extended release rapamycin. Example 2 provides description for the preparation of a particular type of modified polymer (modified alginate) with example 3 providing its use in the hydrogel capsules. However, there is no description outside of the type of formulation, compartment, barrier and modified alginate that are described in applicant’s disclosure. Applicant should put in the structures/formulations that accomplish each of these functional items in claims 1 and 37 as described by applicant to make the operable device. For now, the formulations covered by claims 1 and 37 may include numerous structures and formulations that would provide for varying devices outside of those adequately described by applicant’s disclosure. Thus, applicant does not have possession over the full breadth of such claimed devices that could be capable of these functions. Rather, the description allows for possession of a more particular device that is subject of applicant’s disclosure with examples.
Scope of Enablement
Claims 1-2, 4-5, 9-10, 12-15, 17, 23, 37-38, and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compounds found in claim 18, does not reasonably provide enablement for the full genus of compounds in claim 17 (this is encompassed in broader recitations of claims 1 and 37 where it is indicated they will have a foreign body response mitigation ability. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 17 provides for the structure:
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The structure is given very broad definiton of groups where A can be any alkyl, heteroalkyl, aryl, heteroaryl, etc., M can be absent, alkyl, heteroaryl, cycloalkyl, heterocyclyl, etc, P can be absent, cycloalkyl, heterocyclyl or heteroaryl optionally substituted, and Z can be hydrogen, alkyl, heteroalkyl, aryl or many other broad groups. Applicant provides for compounds of more defined structures as in claim 18. It appears these compounds share certain features like a NH group at one end and structures that relate to compounds that will have FBR (foreign body response) mitigating effects. There is not sufficient enablement for all compounds that can fit in the definitions of formula I in claim 17 that would have such capability in FBR mitigation.
Capuani et al (Bioeng Transl Med, 2022, DOI: 10.1002/btm2.10300, pages 1-22) teaches a review of approaches for foreign body response mitigation (abstract). Capuani teaches a number of considerations including surface topography (2.1), surface charge (2.2), surface wettability (2.3), implant size and shape (2.4), stiffness (2.5) and implantation site (2.6). Sections 4.1 and 4.2 provide for coating strategies with certain polymers and section 4.3 provides for biomimetic coatings. Capuani teaches “Implantable devices have been clinically employed for decades. How ever, there is no gold standard to prevent or modulate the FBR. Therefore, understanding the mechanisms of fibrotic tissue response to implantable devices is fundamental. Implant parameters, including surface wettability, topography, shape, and size, determine the degree of protein adsorption, and the proinflammatory response which may ultimately result in scar tissue formation.” (section 5). Capuani teaches “functionalization or optimization in formulation aimed at improving the biocompatibility of a material can significantly alter its mechanical properties, thus affecting the overall stiffness and durability of the implant” (section 5). In regards to other biomimetic approaches, Capuani notes that “Notably, these findings suggest that mimicking ECM in designing biocompatible implantable devices is a valid strategy to overcome intense FBR. However, the long-term stability of coating materials is still unclear, and requires extensive research” (section 4.3). Thus, the art recognizes a need for research into materials that would be capable of allow foreign body response mitigation. One of skill in the art, which in this case would be a material or polymer chemist, would not have an expectation of success in providing any compound and having it confer such a property.
The applicant does not describe how to make and test for all the compounds encompassed by the genus in claim 17 in foreign body response. It appears that support comes from a prior application that also provides for similar species of compounds within it as well as the same large genus of formula I. Also in claim 17, compound (I) allows for A to be alkyl, L, L2, and L3 to be bonds, M to be absent, P to be absent and Z to be hydrogen, which means the compound can be methane or ethane among other alkanes. Applicant does not show and enable how such compounds can mitigate a foreign body response.
As the state of the art notes more research being needed to find such materials that can mitigate foreign body responses in a patient and the specification is limited on teachings of making and testing compounds found throughout the broad genus claim, there would be undue experimentation needed to make and test every compound of formula I to show that they can indeed mitigate foreign body response. It should be notable that some compounds make an object more susceptible to foreign body responses (e.g. allergens or toxins), and thus, this must be further considered in why one would have to make and test each compound for this purpose as in the claim. Thus, applicant has enablement for the species compounds from the prior art for this purpose, but does not have enablement for all compounds of formula I in claim 17 that can be mitigating of a foreign body response.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4, 5, 9, 10, 12-15, 17, 18, 19, 23, 24, 25, 28, 31, 36-38, 41-42 and 45 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.
Claims 1 and 2 recite the limitation "each immunomodulatory protein" and “each immunosuppressant compound” in the claim with the prior recitations being “at least one immunomodulator protein” and “at least one immunosuppressant compound”. There is insufficient antecedent basis for this limitation in the claim. Applicant may recite “each of the at least one immunomodulator protein” and “each of the at least one immunosuppressant compound”.
Claims 4, 5, 9, 10, 12-15, 17, 18, 19 and 23 are rejected for being dependent on an indefinite claim.
Claim 2 is indefinite for use of “and” to connect these features in the “at least one of the following features” as it is unclear if all of the features i-vii together (via “and”) are needed for the “at least one” or if applicant means each items to be optional of one another with the option of combinations thereof. Applicant may consider using “and/or” rather than “and” after item vi and before item vii.
Claims 4, 5, 9, 10, 17, 18 and 19 are rejected for being dependent on an indefinite claim.
Claim 2 is indefinite for “a FBR-mitigating compound or polymer” as it is unclear if the polymer is also meant to be FBR-mitigating or if the compound if FBR-mitigating and the polymer does not have to be FBR-mitigating. If applicant intends the polymer to also be FBR-mitigating, applicant may recite “a FBR-mitigating compound or a FBR-mitigating polymer…”
Claims 4, 5, 9, 10, 17, 18 and 19 are rejected for being dependent on an indefinite claim.
Claim 2 item vii is indefinite for “any second plurality of genetically modified mammalian cells” as it is unclear if this refers to “a second plurality…” introduced in (i) or if it can be any additional plurality that is included. Applicant may consider amending item vii so that it refers to “….the second plurality…”
Claims 4, 5, 9, 10, 17, 18 and 19 are rejected for being dependent on an indefinite claim.
Claim 2 and 23 is indefinite as it is unclear how a compound can be an extended release formulation. In claim 2, this is found in item (iii). Applicant may amend claim 23 to be “wherein the at least one immunosuppressant compound is a rapamycin compound and wherein the at least one immunosuppressant compound is within an extended release formulation….”
Claims 4, 5, 9, 10, 17, 18, and 19 are rejected for being dependent on an indefinite claim.
Claims 2, 9, 10, 12, and 13 recite the limitations "the immunomodulatory protein(s)" or “the immunosuppressant compound” in the claims when the initial recitations from claim 1 are “at least one immunomodulatory protein” and “at least one immunosuppressant compound”. There is insufficient antecedent basis for this limitation in the claim.
Claims 4, 5, 17, 18 and 19 are rejected as being dependent on indefinite claims.
Claim 37 recites the limitation "the therapeutic substance" in the claim without a prior recitation of “a therapeutic substance”. There is insufficient antecedent basis for this limitation in the claim.
Claims 38, 41, 42, and 45 are rejected for being dependent on an indefinite claim.
Claims 41 and 42 recite the limitation "the compound” in the claim with the prior recitation being “at least one compound”. There is insufficient antecedent basis for this limitation in the claim. Applicant may recite “pharmaceutically acceptable salt of the at least one compound.”
Claims 24, 41 and 42 are indefinite for having a Markush group ending in “, and
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or a pharmaceutically acceptable salt of the compound as the Markush group of elements would be closed to only those compounds found within the group. Thus, it is unclear if applicant wants to allow pharmaceutically acceptable salts to be additional compounds and if the group is truly closed. Applicant may amend the claim to remove the “and” before the last compound structure and to replace the “or” with “and” so that “and a pharmaceutically acceptable salt of the at least one compound.” or alternatively “and a pharmaceutically acceptable salt thereof.” can be read as part of the Markush group.
Claims 25, 28, 31 and 36 are rejected for being dependent on an indefinite claim.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 1-2, 4-5, 9-10, 12-15, 17-19, 23-25, 28, 31, 36-38, 41-42, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Sewell WO2019067766A1, Seo WO2018009047A2, Park et al (Journal of Tissue Engineering and Regenerative Medicine, 2015, volume 11, pages 1174-1284) and Oaks et al (Cellular Immunology, 2000, volume 201, pages 144-153).
Sewell teaches cell compositions comprising an active cell (e.g., an engineered active cell, e.g., an engineered RPE cell) or derivatives thereof, as well as compositions, pharmaceutical products, and implantable elements comprising an active cell, and methods of making and using the same (abstract). Sewell teaches flexible polymers including alginate and modification thereof with compounds of formula I (see Sewell’s claims 26-31). Claim 31 of Sewell includes applicant’s elected compound. Sewell teaches ARPE-19 cells and alginate hydrogel capsules (claims 33 and 34 of Sewell and page 37). Sewell teaches the engineered active cell having exogenous nucleic acid integrated into its chromosome and encoding a polypeptide of various types (claims 22-25 of Sewell). Sewell teaches “a plurality of the implantable element of any one of the preceding claims in a pharmaceutically acceptable carrier.” (claim 35 of Sewell). Sewell teaches “The composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies”. Sewell teaches other pharmaceutical agents including immunosuppressant agents (page 88). Sewell teaches “an engineered RPE cell, are capable of modulating the immune response or the effect of an immune response in a subject” (first paragraph of Summary). Thus, Sewell envisions the engineered cells to modulate the immune response. Sewell teaches the cells producing or releasing therapeutic agents (page 2, lines 15-21). Sewell teaches the implantable element may be injected (page 3, lines 10-14). Sewell teaches enclosing cells in a inflexible polymer (page 3, lines 20-30). Sewell teaches “An "implantable element" as used herein, comprises an active cell, e.g., a plurality of active cells, e.g., a cluster of active cells, wherein the active cell or active cells are entirely or partially disposed within an enclosing component (which enclosing component is other than an active cell), e.g., the enclosing component comprises a non-cellular component. In an embodiment, the enclosing component inhibits an immune attack, or the effect of the immune attack, on the enclosed active cell or active cells. In an embodiment, the enclosing component comprises a semipermeable membrane or a semipermeable polymer matrix or coating.” (paragraph 18). Sewell teaches implantable elements targeting various parts of the body including blood, heart and various other organs (Implantable elements section). Sewell teaches microcarriers in the size range of 10 um to about 5 mm (page 39). Sewell teaches “In some embodiments, the active cells (e.g., RPE cells) produce a plurality of therapeutic agents, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 therapeutic agents. In some embodiments, a cluster of active cells (e.g., RPE cells) comprises active cells that produce a plurality of therapeutic agents. In some embodiments, at least about 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the active cells (e.g., RPE cells) in a cluster produce a plurality of therapeutic agents” (paragraphs 51 and 38 – also different shapes in paragraph 38 including spheroid). Sewell teaches multiple layers such as at least 2 layer, at least 3 layers and others (paragraph 79). Sewell teaches spheroid shape (paragraph 81, lines 26-30). Sewell teaches including pharmaceutically acceptable excipients (paragraphs 84-85). Sewell teaches including the implantable elements into various forms for delivery (paragraph 86). Sewell also teaches “The kits provided may comprise an inventive pharmaceutical composition or device and a container” (paragraph 88).
Although Sewell recognizes that its cells will be engineered to release polypeptides and the cells are able to modulate immune responses while allowing immunosuppressant agents as a pharmaceutical compound to use with the formulation, Sewell does not teach the elected immunomodulator proteins (sFlt3 and sCTLA-4) or rapamycin as the immunosuppressant compound.
Seo teaches a novel DNA vaccine for treating herpes simplex virus-2 (abstract). Seo teaches one or two or more immunity enhancing peptides including Flt3 and CTLA4 (claims 2 and 3 of Seo and paragraph 52, also example 2). Seo teaches genetically modified cells, stably inserted into the genome of a cell, and using eukaryotic cells (paragraphs 39-40). Seo provides for using a secretion signal peptide sequence (claim 4 of Seo). Thus, Seo sees its designed DNA as encoding for peptides/polypeptides including Flt3 (Flt3L is Flt3 ligand, the soluble form) and CTLA4 that are immunity enhancing, which would be useful in subjects with HSV-2 (a viral disease).
Park teaches using alginate coated and rapamycin-PEG coating xenogenic islets with the rapamycin PEG coating being able to improve the biocompatibility of the transplanted microencapsulated cells (abstract). Figure 1 provides for rapamycin concentration over 28 days where the amount increases over the 28 day range (also section 3.1). Thus, this coating provides extended release of rapamycin for the implanted/transplanted microcapsules. Park recognizes rapamycin as an immunosuppressant in its introduction.
Oaks teaches a native soluble form of CTLA-4 which is immunoregulatory (abstract and results). Oaks recognizes the soluble form will have similar useful immune-regulatory properties (page 152, first column).
One of ordinary skill in the art before the time of filing would have modified cells to express various proteins based on the treatment sought for the patient while further incorporating a rapamycin release coating to further protect the implanted cells as Sewell recognizes implanting cells with layer coatings that help to protect the cells while allowing cells to release beneficial proteins for treatment and also being able to include immunosuppressant agents, Seo recognizes a system where cells can be made to express beneficial immunity enhancing proteins including Flt3 ligand and CTLA4 protein for treating HSV-2 (a viral disease) and Park provides for alginate coated cells that are further coated with a PEG-Rapamycin (Park also notes rapamycin as an immunosuppressive agent) extended release coating that is beneficial for improved biocompatibility of the material. Oaks provides for a soluble form of CTLA-4 protein. Therefore, the prior art recognizes purposes for the immunomodulating proteins and immunosuppressant rapamycin in a coating that would provide a benefit to HSV-2 patients while also having improved biocompatibility when implanted into the body. These combined teachings would have led one of ordinary skill in the art to produce the claimed invention with a reasonable expectation of success in obtaining a biocompatible implant with the ability for beneficial treatment of patients.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARK V STEVENS whose telephone number is (571)270-7080. The examiner can normally be reached M-F 9:00 am to 6:00 pm EST.
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/MARK V STEVENS/Primary Examiner, Art Unit 1613
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