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 .
Claim Status
Claims 6-8, 12-13, 15-24, 27-33, 37, 41 and 45 were canceled.
Claims 1-5, 9-11, 14, 25-26, 34-36, 38-40, and 42-44 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/20/2025 is being considered by the examiner. The signed IDS form is attached with the instant office action.
It is noted that NPL document number 5 does not contain retrieved date or published date.
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 35 and 39-40 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.
Claim 35 recites “substantially non-pulsatile release of the antigen molecule” and claim 39 recites “substantially non-pulsatile release of the immune effector molecule”. The term “substantially non-pulsatile” in claims 35 and 39 are a relative term which renders the claim indefinite. The term “substantially non-pulsatile” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what level of pulsatile release is allowed by the term “substantially non-pulsatile”.
Claim 40 recites “the immune effector cell” in line 2. There is insufficient antecedent basis for this limitation in the claim. While claim 1 recites “an immune effector molecule”, claim 1 does not recite “an immune effector cell”.
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.
Claims 1-5, 9-11, 14, 25-26, 34-36, 38-40, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Jarvis et al (US4680174; IDS) in view of Shin et al (US2017/0196818; IDS) and Yan et al (Immunotherapy (2017) 9(4), 347-360; PTO-892) as evidenced by Yu et al (Journal of Colloid and Interface Science 539 (2019) 497-503; PTO-892).
Regarding claim 1-2, 9 and 14, Jarvis teaches “Cells such as genetically modified cells, e.g., hybridoma, which secrete an antigenic substance are encapsulated within capsule membranes (corresponds to “layer” of instant claim 14) having pores of dimensions sufficient to permit efflux of the antigens secreted by the cells but insufficient to permit traverse of the cells. The capsules are injected into an experimental animal (corresponds to “first implantable construct” of claim 1) where antigen passing through the pores of the capsule membrane induces lymphocytes to produce antibodies complementary to the antigen (corresponds to “induces am immune response in a subject” of instant claim 2)” (abstract). Because antigen-producing cell was injected into the experimental animal, the antigen is exogenous antigen as recited by instant claim 9.
Regarding claim 3, Jarvis teaches that antigen secreted by encapsulated cell is a glycolipid, glycoprotein, lipoprotein, polysaccharide or protein (claim 17 and 28).
Regarding claim 25-26, Jarvis teaches “the permeability of the membrane can be controlled in part by selecting the molecular weight of the cross-linking polymer used, the duration of the cross-linking steps, and the concentration of polymer in the cross-linking solution”. Jarvis teaches “Depending on the type of semipermeable membrane formation technique employed, it is often desirable to treat the capsules so as to occupy free amino groups or the like which might otherwise impart to the capsule a tendency to clump. This can be done, for example, by immersing the capsule in a solution of sodium alginate.” Jarvis teaches “The BALB/c hybridoma (designated C25) was suspended in a 1.34% (w/v) sodium alginate (NaG-Kelco) in saline solution” (example 1).
Regarding claims 35 and 39, as evidenced by Yu, alginate encapsulation of Jarvis and Shin (see below; invention of Shin also comprises alginate encapsulation) provides sustained non-pulsatile release. Yu teaches “Alginate hydrogel particles are promising delivery systems for protein encapsulation and controlled release because of their excellent biocompatibility, biodegradability, and mild gelation process” (abstract). Yu shows that alginate encapsulation provides non-pulsatile release of ovalbumin over several days (Figure 6(d); reproduced below).
PNG
media_image1.png
543
632
media_image1.png
Greyscale
Regarding claim 44, Jarvis teaches “A process for inducing an immune response in an animal body, said process comprising the steps of: A. providing a living cell which secretes an antigen capable of inducing an immune response in said animal body; B. encapsulating said cell within a membrane comprising pores and defining an intracapsular volume with which said cell is suspended; C. controlling the dimensions of the pores to permit passage therethrough of said antigen but to preclude passage therethrough of said cell; D. implanting said encapsulated cell in said animal body; E. permitting said secreted antigen to traverse said membrane within said animal body to induce an immune response; and F. harvesting an antibody complementary to said antigen from the circulatory system of said animal body” (claim 1).
The difference between prior art and the instant invention is that Jarvis does not teach the second implantable construct producing immune effector molecule. As shown below, the second implantable construct producing immune effector molecule is taught by Shin and the rationale to combine two implantable constructs producing antigen and immune effector molecule are taught by Yan.
Regarding claim 1 and 10-11, Shin teaches “A method of administering at least one protein factor produced by a cell to a subject in need thereof, the method comprising administering to said subject a composition comprising a plurality of hydrogel capsules, wherein at least 90% of said hydrogel capsules in said composition comprise a cell and a hydrogel encapsulating said cell (corresponds to “second implantable construct comprising an engineered cell” of instant claim 1), wherein said hydrogel encapsulating said cell has a thickness of less than 20 microns” (claim 24). Shin teaches “The method of claim 24, wherein the cell is a mesencymal stem cell (MSC) or a progenitor thereof” (claim 25). Shin teaches “The method of claim 25, wherein said at least one protein factor is a hematopoietic factor selected from the group consisting of stem cell factor (SCF), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-7 (IL-7), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), erythropoietin, thrombopoietin, collagen-I, interleukin-11 (IL-11), angiopoietin-1 and transforming growth factor-beta (TGF-beta)” (claim 31). Shin teaches “In some embodiments, the composition is administered by … subcutaneous implantation” [0027].
Regarding claim 34 and 38, Shin teaches a composition comprising a plurality of hydrogel capsules, wherein at least 90% of said hydrogel capsules in said composition comprise a cell and a hydrogel encapsulating said cell (claim 1). Shin teaches that the hydrogel comprises alginate (claim 5 and 7). Shin teaches “The hydrogel encapsulated cells are also characterized by improved cell viability and are capable of sustained secretion of protein factors” [0007]. Because encapsulating membrane of Jarvis also comprises alginate as discussed above and the same encapsulating material alginate has property of sustained secretion as taught by Shin, the encapsulating membrane of Jarvis will also provide sustained secretion of antigen molecule as recited by instant claim 34 because sustained release is the functional property of the encapsulating membrane which comprises same material alginate as the invention of Shin.
Regarding claim 36 and 40, Shin teaches “Injection of cells encapsulated in the higher, 232-kDa MW polymer increased the total concentration of human IL-6 in blood plasma at 24 hours by ˜2 fold, as compared to unencapsulated cells (FIG. 25D)” [0364]. Therefore, Shin teaches the release of immune effector molecule for at least 1 day. As discussed above, because the encapsulating membrane of both Jarvis and Shin are composed of same polymer alginate and the release of antigen and immune effector molecule is the functional property of the encapsulating membrane, the encapsulating membrane of Jarvis will also provide release of the antigen molecule for at least 1 day as recited by instant claim 36.
Furthermore, Yan teaches the rationale to combine implantable construct producing antigen and second implantable construct producing immune effector molecule.
Regarding claim 4 and 5, Yan teaches “Cancer immunotherapy is a growing field. GM-CSF, a potent cytokine promoting the differentiation of myeloid cells, can also be used as an immunostimulatory adjuvant to elicit antitumor immunity (corresponds to “enhances an immune response in a subject” of instant claim 5). Additionally, GM-CSF is essential for the differentiation of dendritic cells, which are responsible for processing and presenting tumor antigens for the priming of antitumor cytotoxic T lymphocytes” (abstract). Yan teaches “GM-CSF has also been shown to promote DC expansion and activation”. Therefore, Yan teaches that immune effector molecule (e.g. GM-CSF) activates an immune cell (e.g. dendritic cell) as recited by instant claim 4.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the first implantable construct of Jarvis producing antigen and the second implantable construct of Shin producing cytokine in order to make a combination composition because Yan teaches that cytokines can be used as an immunostimulatory adjuvant to elicit antitumor immunity. Because Yan teaches that cytokines enhance an immune response, one of ordinary skill in the art would be motivated to combine cytokine-producing second implantable construct to the first implantable construct producing antigen to enhance immune response against the antigen. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
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 because Yan teaches that cytokines can be used as an immunostimulatory adjuvant to elicit antitumor immunity. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-5, 9-11, 14, 25-26, 34-36, 38-40, and 42-44 are rejected under 35 U.S.C. 103 as being unpatentable over Jarvis et al (US4680174; IDS) in view of Shin et al (US2017/0196818; IDS) and Yan et al (Immunotherapy (2017) 9(4), 347-360; PTO-892) as applied to claims 1-5, 9-11, 14, 25-26, 34-36, 38-40, and 44 above, and further in view of Toubaji et al (Vaccine 25 (2007) 5882-5891; PTO-892).
Regarding claims 1-5, 9-11, 14, 25-26, 34-36, 38-40, and 44, teachings of Jarvis, Shin and Yan were discussed above.
The difference between prior art and the instant invention is that Jarvis, Shin and Yan do not teach composition comprising the three implantable constructs as recited by instant claim 42 and 43.
Regarding claims 42 and 43, Toubaji teaches “Many strategies have been used to enhance the peptide vaccine immune response and to establish therapeutic benefits. This includes the utilization of cytokines to improve antigen presentation or enhance T cell response. Here, we have tested the combination of GM-CSF and IL-2 as locally administered adjuvant to enhance the immune response to the HPV16 E7 peptide. Female C57BL/6 mice were immunized intradermally with a 9-mer HPV16 E7 peptide (aa: 49-57) alone, or in combination with GM-CSF, IL-2, or both cytokines. Specific immune responses were measured by ELISA and Chromium-Release Assays. Furthermore, therapeutic effects of these vaccines and long-term tumor protection were assessed in mice bearing established tumors. We showed that GM-CSF and IL-2, when co-administered locally in an emulsion with peptide, exert a synergistic effect in enhancing the immune response to the antigen. This combination induced higher CTL and cytokine release responses and did not increase the T(reg) population. Therapeutic intervention with this synergistic combination led to a complete response of established tumors. Furthermore, this combination induced a memory response which protected mice against subsequent additional tumor challenge. We identified a new vaccine adjuvant, a local combination of GM-CSF and IL-2, which is synergistic in enhancing peptide specific immune response through local effect without increasing T(reg) cells. This immune response was found to be long lasting and protective in tumor bearing mice” (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a third implantable construct producing IL2 to the composition of Jarvis and Shin comprising first and second implantable constructs producing antigen and GM-CSF because Toubaji teaches that combination of GM-CSF and IL2 as a vaccine adjuvant exerts a synergistic effect in enhancing the immune response to the antigen. One of ordinary skill in the art would be motivated to test this same combination of cytokines as vaccine adjuvant will also work in the system of implantable constructs comprising encapsulated engineered cell producing antigen and cytokines. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
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 because Toubaji teaches that combination of GM-CSF and IL2 as a vaccine adjuvant exerts a synergistic effect in enhancing the immune response to the antigen. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHEOM-GIL CHEONG whose telephone number is (571)272-6251. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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, Daniel Kolker can be reached at 571-272-3181. 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.
/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645