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 .
Formalities:
The specification of 5/9/24 is accepted.
The drawing of 5/9/24 is accepted.
The IDS filings of 5/9/24 and 11/27/24 and references therein have been considered. A signed copy of each IDS filing is provided herewith.
Applicant’s priority is noted to be:
This application is a DIV of 17/052,830 11/04/2020
17/052,830 is a 371 of PCT/US2019/030585 05/03/2019
PCT/US2019/030585 has PRO 62/666,786 05/04/2018
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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*it should be noted that the restriction in the 18/659,833 Application has been rejoined between the method of administering and the method of making the compositions.
Claims 27-29 and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-29 and 31-32 of copending Application No. 18/659,833 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 27: Claim 19 teaches treating a patient with cancer, by administering the composition of Claim 1. Claim 1 teaches making fibroblasts by way of modification to comprise one more tumor inhibitory agents. The agents are seen Claims 12-13 to be oncolytic/tumor trophic viruses, and in Claim 15 to be a vector encoding several distinct proteins.
Claims 28-29: Claim 6 teaches the fibroblasts may be modified to express the same Markush of chemokine receptors.
Claim 31: Claim 12 teaches the tumor trophic/oncolytic virus.
Claim 32: Claim 15 teaches the same Markush of tumor inhibitory agents.
Thus, in light of the reference, the invention is obvious. The Artisan would make it and expect success, as it is claimed subject matter.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
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 27-29 and 31-32 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.
The claims, as seen by depending Claim 31 are generic for the “tumor trophic virus”.
The specification provides no definition for what a tumor trophic virus is. However, it provides repeated recitations of the claim terminology “oncolytic or tumor-trophic virus”, e.g., paragraphs 39, 41, and 48 (the sole recitations for “tumor trophic”). Examples are given, listing adenovirus, vaccinia, herpes, reovirus, measles and Newcastle Disease Virus (e.g., paragraph 48). The same paragraph cites the bibliography citations 9-26, however, in reviewing these, these are all oncoviruses. Thus, the recitation of “tumor trophic virus” being an alternative listing to that of oncovirus, due to the conjunction “or”, must necessarily rely on the art for the elucidation of this genera of virus.
However, the Art fails to provide any description whatsoever of “tumor trophic virus”. However, if one were to look at the words themselves, it would be tumor-eating-virus, i.e., a virus that works on tumors with preference. Such is exactly the same as an oncolytic virus.
Thus, due to the lack of description in the art, as well as in the specification, the Artisan would not have understood Applicant to have been in possession of a generic “tumor trophic virus” as a class distinct from that of “oncovirus”.
Claim Rejections - 35 USC § 112
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 1-7, 11-19, and 22-25 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.
The claims are generic for a fibroblast (e.g., Claim 27) infected with a vector (e.g., Claim 27) and an oncolytic/tumor-trophic virus (e.g., Claim 31).
The specification makes clear the purpose for the oncovirus in the fibroblast so-made is to deliver the oncovirus to the cancer cells (e.g., paragraph 48). The specification also discloses in Example 2 that fibroblasts infected with Newcastle disease virus were very effective in inhibiting tumor growth of B16-BL6 tumor cells in C57/B6 mice (paragraphs 110-113), where the virus itself did not affect tumor growth at all, even at concentrations as high as 2x10⁵ PFU per mouse (Id.).
This is perplexing, as the NDV itself is known to cause oncolysis in these cancer cells, by lysing them, while not growing in non-cancer cells. Still further, it is known in the art that fibroblasts like cancer-associated fibroblasts may be infected by oncolytic viruses but are non-permissive to viral replication (e.g., Kaufman, et al. (2016) "Oncolytic viruses: a new class of immunotherapy drugs", Cancer Immunotherapy, 14: 642-62, p. 647, col. 1). Thus, it is apparent that something else is going on here. It would appear the fibroblasts are not delivering the oncovirus to the cancer cells. Such is bolstered by Applicant's finding that the oncovirus itself is ineffective at treating the cancer, as seen in the same Example. What exactly is happening is not known, however.
Moreover, distinct oncoviruses contain distinct mechanisms in their functioning. Fountzilas, et al. (2017) "Review: Oncolytic virotherapy, updates and future directions" Oncotarget, 8(60): 102617-39 provides an overview of oncolytic virotherapy for cancers, which includes oncolytic adenoviruses and vaccinia (e.g., Table 1A). The review provides for distinct cancer types for any particular oncolytic virus (whole article). Each one has distinct mechanisms of action and different proteins interacting. These oncolytic viruses have a plethora of different mechanisms (e.g., p. 102618, col. 1). Moreover, they are effective in distinct cancer types (e.g., Tables 1A-2B, whole article). Thus, distinct chemistries exist and one would not know that one oncovirus would interact properly in the non-permissive fibroblast to cause a delivery (i.e., it would need to form a new virus) or to otherwise cause a therapy.
Thus, outside the treatment of the melanoma in mice, with the fibroblasts infected with NDV, as in the examples, the Artisan would not know, given the breadth of cancers and oncoviruses and distinct chemistries of these oncoviruses, that Applicant possessed the generic fibroblast infected with a generic oncolytic virus.
Claim Rejections - 35 USC § 112
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 27-29 and 31-32 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 NDV, hypoxia and the fibroblast type utilized in the examples, does not reasonably provide enablement for any virus, any oncovirus, any fibroblast, or the absence of hypoxia. 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/use the invention commensurate in scope with these claims.
The claims are broad for the species of oncolytic viruses encompassed in the species of fibroblasts, as well as the absence of hypoxia on cancer associated fibroblasts.
The specification makes clear the purpose of the oncovirus in the fibroblast is to deliver the oncovirus to the cancer cells (e.g., paragraph 48). The specification also discloses in Example 2 that fibroblasts infected with Newcastle disease virus were very effective in inhibiting tumor growth of B16-BL6 tumor cells in C57/B6 mice (paragraphs 110-113), where the virus itself did not affect tumor growth at all, even at concentrations as high as 2x 10⁵ PFU per mouse (Id.).
This is perplexing, as the virus itself causes oncolysis in the cancer cells, by lysing them, while not existing in non-cancer cells. Still further, it is known in the art that fibroblasts that are cancer-associated fibroblasts may be infected by oncolytic viruses but are non-permissive to viral replication (e.g., Kaufman, et al. (2016) "Oncolytic viruses: a new class of immunotherapy drugs", Cancer Immunotherapy, 14: 642-62, p. 647, col. 1). Thus, it is apparent that something else is going on here. It would appear that the fibroblasts are not delivering the oncovirus. Such is bolstered by Applicant's finding that the oncovirus itself is ineffective at treating the cancer. What exactly is happening is not known, however. Still further, Applicant’s examples utilize hypoxia only, in the growth of the fibroblasts. The Art recognizes that hypoxia inactivates CAFs to work against cancer (e.g., Madsen, et al. (2015) “Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumor stiffness and metastasis”, EMBO reports, 16(10): 1394-408). Thus, it would appear that hypoxia is required for at least these fibroblast types, prior to delivery, or the only thing it would do is enhance tumor metastasis.
Moreover, distinct oncoviruses contain distinct mechanisms in their functioning. Fountzilas, et al. (2017) "Review: Oncolytic virotherapy, updates and future directions", Oncotarget, 8(60): 102617-39 provides an overview of oncolytic virotherapy for cancers. The review provides for many distinct cancer types for any particular oncovirus (whole article). Each one has distinct mechanisms of action and different proteins interacting. These oncolytic viruses have a plethora of different mechanisms (e.g., p. 102618, col. 1). Moreover, they are effective in distinct cancer types (e.g., Tables 1A-2B, whole article). Thus, distinct chemistries exist and one would not know that one oncovirus would interact properly in the non-permissive fibroblast to cause a delivery (i.e., it would need to form a new virus) or to otherwise cause a therapy. As can be seen, the mechanisms being distinct would mean that the effect of one may not translate to another virus.
From this, we see that the Artisan would not reasonably predict that any oncovirus would work with any form of cancer, when delivered by fibroblasts. Further, the Artisan would not reasonably predict that any particular cancer-associated fibroblast would be effective when infected with any particular oncolytic virus.
Further, there exist many known oncolytic viruses (e.g., Lundstrom (2018) "New Frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy", Biologics: Targets and Therapy, 12: 43-60, Tables 1-2, teaching a portion of the known oncolytic viruses in the art). However, Applicant's amended claims are to herpes, reovirus, measles or Newcastle Disease Virus. But even within these, the mechanisms of action of any particular oncovirus is distinct. For example, Measles virus appears to be involved in autophagy and/or apoptosis, but the mechanisms are still under debate, even after the filing of Applicant (Pidelaserra-Marti, et al. (2020) "Mechanisms of measles virus oncolytic immunotherapy", Cytokine and Growth Factor Reviews, 56: 28-38, e.g., p. 29, col. 2, paragraph 2), while reovirus also has a limited understanding of the factors that determine oncolysis, with gene segments L2 L3 and M1 appear to be involved with enhance cell killing of carcinoma cells, while S4 may be involved with Ras-transformed cells (Phillips, et al. (2018) "Current understanding of reovirus oncolysis mechanisms", Oncolytic Virotherapy, 7: 53-63, e.g., pp. 57, col. 2 to 58, paragraph 1).
Because the Artisan would have to experiment with the full scope of oncolytic viruses
beyond that of NDV for melanoma, to determine if they would treat a cancer when delivered by a Fibroblast, and determine if they would be effective in a cancer-associated fibroblast, and hypoxia is required or not in each case, such is considered undue as it is required for the vast majority of the viruses in the scope of the claims.
Thus, outside the treatment of the melanoma in mice, with the fibroblasts infected with NDV of the examples, and performed with hypoxia, the claims are only considered enabling for NDV in non-cancer-associated fibroblasts.
Claim Rejections - 35 USC § 112
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 27-29 and 31-32 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.
The claims are generic for the fibroblasts modified generically to upregulate expression of one or more chemokine receptors (e.g., Claim 28). Specific modification claimed includes expressing a chemokine receptor (e.g., Claim 5), CXCR4, CXCL16, and/or CCL9 (e.g., Claim 6).
The specification provides antecedent basis for a generic modification of fibroblasts to home to cancer cells/tissue (e.g., paragraph 6) and specifically lists chemokine receptors and the claimed specific receptors (e.g., Id.). No other form of modification to home to cancer is taught.
The Art at the time of invention had already established that certain cells, when transfected a chemokine receptor for a chemokine secreted by tumor tissue, would so-migrate to the tumor in vivo. For example, Muller, et al. (2015) “Engineering NK Cells Modified With EGFRvIII-specific Chimeric Antigen Receptor to Overexpress CXCR4 Improves Immunotherapy of CXCL12/SDF-1-[alpha]-secreting Glioblastoma”, Journal of Immunotherapy, 38: 197-210, ABSTRACT, teaches the transfection of NK cells to express CXCR4 conferred specific chemotaxis to CXCL12/SDF-1[alpha] expressing glioblastoma cells. Moreover, there is art discussing the ability to use chemokine receptors to stimulate migration of cells (e.g., Hughes, et al. (2018) “A guide to chemokines and their receptors”, The FEBS Journal, 285: 2944-71, ABSTRACT). Thus, the Artisan would be aware that fibroblasts could be so-targeted to the cancer by way of proper cytokine/receptor selection.
On the other hand, the Art is silent with regard to other ways to modify such cells to upregulate the expression of the endogenous genes encoding chemokine receptors. For example there is no discussion in the art of which transcription, splicing, pre-mRNA modifying proteins, translation initiation proteins, and degradation proteins are targeted and how to specifically upregulate the various chemokine receptors.
The Artisan would not have found applicant to have been in possession of other forms of modification to target cancer cell types, beyond that of recombinant expression of chemokine receptors, given that the only know way to do so is by way of chemokine receptors that respond to the chemokines secreted by the cancer/tissue.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 11-12, 14, and 18-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jing, et al, Abstract 3745, “Tumor fibroblast targeting via uPAR retargeted measles virus: In vitro and in vivo effects”, Cancer Research, 15 July 2016, 76(14 Supplement): 3745, 3 pages as printed.
Claims 17 and 31: Jing teaches retargeted oncolytic measles viruses directed to human and marine uPAR. In the disclosure, these oncolytic measles viruses were infected into human and marine fibroblasts (human CAF 19 and CAF 23 cells) (ABSTRACT). And, the modified fibroblasts are injected into mice with a human breast cancer xenograft and it reduced tumor progression, demonstrating an effective amount was utilized (ABSTRACT).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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