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 .
Claim Status
Claims 21 and 27 are amended.
Claims 28-35 are cancelled.
Claim 41 is new.
Claims 21-25,27, and 36-41 are pending.
Rejections Withdrawn
Claim Rejections - 35 USC § 102
The rejections of claims 21,22,25,27,31,35, and 40 are under 35 U.S.C. 102(a)(1) as being anticipated by Fidai et al ( WO 2018/234862 A1) is withdrawn in light of claims amendment.
Claim Rejections - 35 USC § 103
The rejections of claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Fidai et al ( WO 2018/234862 A1), in view of Bortolanza et al ( Cancer Gene Therapy,2009) is withdrawn in view of claims cancellation.
The rejections of claims 28,32-34 under 35 U.S.C. 103 as being unpatentable over Fidai et al ( WO 2018/234862 A1), in view of Kawakami et al ( Cancer Research, 2003) is withdrawn in view of claims cancellation.
The rejections of claims 23-24, and 36-39 under 35 U.S.C. 103 as being unpatentable over Fidai et al ( WO 2018/234862 A1), in view of Havunen et al ( Molecular Therapy: Oncolytic, 2017), and Levin et al (Nature,2012) is withdrawn in view of claims amendment.
Response to Amendments
Applicant’s arguments have been carefully considered and found persuasive. The new ground of rejection below addresses the deficiencies raised by Applicant with respect to the amended claims.
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 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.
Claims 21,22,25,27, and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Fidai et al ( WO 2018/234862 A1), in view of Bortolanza et al ( Cancer Gene Therapy,2009), Kawakami et al (Cancer Research, 2003), and Liu et al ( Molecular Therapy, 2004).
Regarding claim 21, Fidai et al disclose a method of treating a subject having cancer by administering a pharmaceutical composition comprising an IL-2 mutein (also known as IL-2 superkine) conjugated to or expressed by an oncolytic virus, where the oncolytic virus is capable of targeting a cancer cell (i.e. a therapeutic oncolytic virus). (See paragraphs [0007], and [0040]). Fidai et al disclose that the expressed IL-2 mutein has amino acids substitutions that include L80F, R81D, L85V, I86V and I92F. It should be noted that the SEQ ID NO:2 disclosed by Fidai et al is 100% identical to SEQ ID NO: 2 of instant application. Therefore, IL-2 mutein taught by Fidai is the same variant interleukin 2 (vIL-2) of the instant application, as both contain the exact amino acids substitutions made to the wildtype IL-2.(See paragraphs [0030], [0058], [00100], and page 11 for SEQ ID NO:2).
Fidai et al also teach that the backbone of the adenovirus is an oncolytic adenoviral derived from adenovirus type 5 (Ad-5) with a 24-base-pair deletion (i.e. Ad5-d24 backbone). (See paragraphs [00190-00192]). Furthermore, Fidai et al disclose that the backbone of the oncolytic adenoviral vector involves “the replacement of the basic adenovirus E1a promoter with a basic promoter that exhibits tumor specificity, and preferably is E2F responsive, and more preferably is the human E2F-1 promoter”.(See paragraph [00193]). Taken together, the backbone of Fidai’s oncolytic vector include i.e. Ad5-E2F-d24 to drive the expression of IL-2 mutein. However, Fidai et al do not teach the use of a chimeric Ad5/3 vector comprising of adenoviral serotype 5 (Ad5) with the fiber knob of the adenoviral serotype 3 (Ad3).
Kawakami et al disclose that, while adenovirus serotype 5 is the most commonly used vector for cancer gene therapy, many tumor types are refractory to Ad5 infection due to low surface expression of the native Ad5 receptor. To address this issue, Kawakami et al demonstrate that the tropism of Ad5 to various types of tumors can be modified by creating a chimeric adenovirus in which the Ad5 is modified by substituting the knob region from other Ad
Serotypes, such as Ad type 3 (Ad3), into the Ad5 fiber region (i.e. Ad5/3 fiber knob). Kawakami et al show that the engineered chimeric vector Ad5/3 virus replicated more efficiently and had better therapeutic efficacy in a murine in vivo tumor rejection model than its Ad5 counterpart. ( See abstract, Fig.3, and Fig.5).
Therefore, the use of a vector comprising of Ad5/3-F2F-d24 backbone is a product of combining prior art elements according to known methods to yield predictable results. Fidai et al teach a method for the treatment of cancer in a subject comprising administering oncolytic adenoviral vector containing a nucleic acid encoding IL-2 mutein, Fidai et al further suggest the use of oncolytic vector comprising Ad5-E2F-d24 to drive the expression of IL-2 mutein, but fails to suggest the use of a chimeric vector comprising Ad5/3. Kawakami et al disclose that the tropism of Ad5 to different types of tumors can be modified by generating a chimeric adenovirus comprising Ad5/3 fiber knob. Thus, one would have been motivated to use a chimeric Ad5/3 oncolytic virus, as disclosed by Kawakami, to deliver IL-2 mutein polypeptide for treating cancer in a subject, as disclosed by Fidai. A person of ordinary skill in the art who had reviewed Fidai could have come across Kawakami and immediately noticed the strong possibility that the use of Ad5/3 vector, instead if Ad5 vector of Fidai et al, would have predictable results of generating vector with an increased tropism to various types of tumors and improves infection and subsequent oncolytic replication, which is especially relevant in gene therapy applications for tumors that are inefficiently infected with Ad5.
Furthermore, Fidai et al do not teach the use of the E3 region within the adenovirus’s backbone as an insertional locus for the transgene, which would replace the gp19k and the 6.7k (gp19k/6.7k) open reading frame.
Bortolanza et al disclose an insertional locus within the adenovirus E3 region that allows therapeutic genes to be incorporated into the backbone of the oncolytic adenovirus without altering the virus’s property. The suggested locus includes a partial deletion of the adenovirus E3 region, which contains the overlapping gp19k/6.7k genes, allowing for the insertion of up to 2.5 kb genetic material. Bortolanza et al demonstrate that this deletion prevents significant disruption of other genes in the E3 region and ensures strong transgene expression without reducing the virus replication or cytolytic potency. Bortolanza et al further disclose that because E3-gp19k and 6.7k proteins are involved in avoiding recognition and elimination of infected cells by the host immune system, the lack of E3-gp19k and 6.7k genes has accelerated the clearance of oncolytic adenoviruses in immunocompetent tumor models. (See abstract).
Therefore, inserting the IL-2 mutein within the E3 region of the adenovirus’s backbone is also a product of combining prior art elements according to known methods to yield predictable results. Because, Fidai et al teach a method for the treatment of cancer comprising administering oncolytic adenoviral vector containing a nucleic acid encoding IL-2 mutein, but fails to teach inserting the transgene encoding for the IL-2 mutein within the E3 region of the oncolytic vector. Bortolanza et al disclose that a therapeutic transgene can be inserted within the adenovirus E3 region, replacing gp19K /6.7k region, without reducing virus replication and cytolytic potency. Therefore, an ordinary skill in the art at the time the invention was filed would have been motivated to insert the transgene encoding for the IL-2 mutein, as disclosed by Fidai, within the E3 region, replacing the E3-gp19K and 6.7K region, as disclosed by Bortolanza, because such replacement would produce predictable results of ensuring strong transgene expression without reducing adenovirus replication and cytolytic potency.
In addition, Fidai et al do not teach an oncolytic adenovirus backbone lacking the E1B-19 K gene region.
Liu et al teach that in wildtype adenovirus the E1B-19 K gene is involved in blocking apoptosis induction via the intrinsic and extrinsic pathways, specifically the cell death pathway mediated by the tumor necrosis factor (TNFα). Liu et al demonstrate that the deletion of the E1B-19 K gene from the backbone of oncolytic adenovirus resulted in marked selectivity for tumor cells compared to normal healthy cells, and enhanced replication and efficacy in tumor tissue. (See Fig.1-2). Liu et al teach that this enhanced activity is likely due to the mutant virus’s inability to fully suppress apoptotic pathway in tumor cells, making it more vulnerable to TNF-induced stress and killing mechanisms. (See discussion). Liu et al also demonstrate that the deletion of E1B-19 K from the backbone of the oncolytic adenovirus resulted in a significant reduction in its systemic toxicity, especially hepatotoxicity, with a concomitant increase in intratumoral replication. ( See Fig.5). Liu et al further suggest that “ E1B-19 K deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy”. See abstract.
Therefore, deleting the E1B-19 K gene from the backbone of the oncolytic adenovirus is also a product of combining prior art elements according to known methods to yield predictable results. Because, Fidai et al teach a method for the treatment of cancer comprising administering oncolytic adenoviral vector containing a nucleic acid encoding IL-2 mutein, but fails to teach deleting the E1B-19 K gene from the virus backbone. Liu et al demonstrate that the deletion of the E1B-19 K gene from the backbone of oncolytic adenovirus resulted in marked selectivity for tumor cells compared to normal healthy cells, and enhanced replication and efficacy in tumor tissue, and further suggest that the E1B-19 K deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy. Therefore, an ordinary skill in the art at the time the invention was filed would have been motivated to delete the E1B-19 K gene from the backbone of adenovirus vector, as taught by Liu et al, and use the vector to deliver IL-2 mutein for the treatment of cancer, as disclosed by Fidai, because doing so would produce predictable results of producing a therapeutic oncolytic adenovirus vector with an enhanced safety, spread, and efficacy.
Regarding claims 22 and 41, Fidai et al disclose that the method of treating cancer using the therapeutic oncolytic adenovirus armed with IL-2 mutein includes a subject having cancer selected from the group consisting of prostate cancer, ovarian cancer, breast cancer, endometrial cancer, multiple myeloma, melanoma, lymphomas, lung cancers including small cell lung cancer, kidney cancer, liver cancer, colon cancer, colorectal cancer, pancreatic cancer, gastric cancer, and brain cancer. (See claim 14).
Regarding claim 25, The method of Fidai et al further includes the concurrent administration of antibody, ionizing radiation, or chemotherapeutic agents; wherein the administration is simultaneously or sequentially. (See abstract, and paragraphs [00319], [00324]).
Regarding claim 27, The IL-2 mutein taught by Fidai et al contains the same amino acids substitutions as the vIL-2 of instant application (i.e. L80F, R81D, L85V, I86V and I92F ). Fidai et al teach that these substitutions results in IL-2 variant with higher binding affinity to IL-2Rβ/IL2Rγ. (See paragraphs [00104] and [00107]). Fidai et al also disclose that the engineered IL-2 mutein has lower or ablated binding affinity to IL-2Rα (also termed CD25) compared to wild-type IL-2.( See paragraph [00112]) .
Regarding claim 40, Fidai et al also teach that IL-2 muteins” can be incorporated into compositions, including pharmaceutical compositions. Such compositions typically include the polypeptide or nucleic acid molecule and a pharmaceutically acceptable carrier”. (See paragraph [00322],and [00326]).
Claims 23-24, and 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Fidai et al, in view of Bortolanza et al, Kawakami et al, and Liu et al as applied to claims 21,22,25,27, and 40-41 above, and further in view of Havunen et al ( Molecular Therapy: Oncolytic, 2017), and Levin et al (Nature,2012).
Regarding claims 23-24, following the discussion of claim 21 above, Fidai et al in view of Bortolanza, Kawakami, and Liu render obvious an oncolytic adenovirus vector encoding IL-2 mutein for the treatment of cancer in a subject. However, Fidai et al do not teach the combined administration of IL-2 mutein-armed oncolytic adenovirus and adoptive cell therapy.
Havunen et al utilize a therapeutic oncolytic adenovirus encoding for human IL-2 to improve and broaden the applicability of adoptive cell transfer. As such, Havunen et al demonstrate that administering IL-2-armed oncolytic adenovirus alongside adoptive cell therapy produces a synergistic therapeutic effect and improves the curative efficacy of adoptive cell therapy in immunocompetent Syrian Hamsters. (See abstract, and Fig.4C). The teachings of Havunen et al differs from Fidai et al in that they use wildtype human IL-2 rather than IL-2 mutein.
Levin et al disclose that interleukin-2 (IL-2) is an immunostimulatory cytokine that acts as a growth factor for a variety of leukocytes, including T cells and natural killer (NK) cells, and is therefore widely used as a cancer therapeutic agent. Levin et al teach that IL-2 signals
through a receptor complex consisting of IL-2Rα (also termed CD25), IL-2Rβ, and IL-2Rγ. According to Levin, naive T cells have low density of IL-2Rβ and IL-2Rγ, making them relatively insensitive to IL-2, but acquire sensitivity after IL-2Rα expression, which captures the cytokine and presents it to IL-2Rβ and IL-2Rγ. To eliminate the functional requirement of IL-2 and CD25 interaction, Levin et al engineered IL-2 superkine with increased binding affinity to IL-2Rβ. It should be noted that IL-2 superkine is also termed “ IL-2 mutein, as disclosed by Fidai” and vIL-2, as disclosed in the instant application. Levin et al demonstrate that the engineered IL-2 superkine recapitulated the CD25’s functional role by inducing vigorous T cell proliferation irrespective of CD25 expression. Levin et al also teach that , when compared to wildtype IL-2, the IL-2 superkine induced greater expansion of cytotoxic T cells, resulting in improved antitumor responses in vivo, while eliciting proportionally less expansion of T-regulatory cells and reducing pulmonary oedema. (See abstract).
Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to combine the teachings of Fidai, Havunen, and Levin to use a combination therapy consisting of “IL-2 mutein”-armed oncolytic adenovirus and adoptive cell therapy for treating cancer in subject. Because Fidai et al teach a method for the treatment of cancer in a subject comprising administering oncolytic adenoviral vector containing a nucleic acid encoding IL-2 mutein. Havunen et al demonstrate that the combined administration of IL-2-armed oncolytic adenovirus with adoptive cell therapy produces a synergistic therapeutic effect in immunocompetent Syrian Hamsters. Levin et al teach that IL-2 superkine induces superior expansion of cytotoxic T cells but proportionally less expansion of T-regulatory cells , leading to improved antitumor responses in vivo. Thus, one would have been motivated to use “IL-2 mutein” -armed oncolytic adenovirus, as disclosed by Fidai and suggested by Levin, in combination with adoptive cell therapy, as disclosed by Havunen, for treating cancer in a subject, because doing so would produce a synergistic therapeutic effect and improve the curative efficacy of adoptive cell therapy. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Regarding claims 36-39, Following the discussion of claims 23-24, the combined teachings of Fidai, Havunen, and Levin render obvious the use of IL- 2 mutein over the wildtype IL-2. However, Fidai et al do not teach an adenovirus vector encoding a second transgene, wherein the transgene is a cytokine.
Havunen et al utilized an oncolytic adenovirus encoding both IL-2 and TNF-α to treat cancer in a subject, this reads on claims 36-39. Havunen et al teach that arming the oncolytic adenovirus with IL-2 and TNF-α resulted in a significant antitumor efficacy against human tumors in immunocompromised severe combined immunodeficiency(SCID) mice. (See Fig.3b-C). Havunen et al also teach that arming with IL-2 and TNF-α increased CD4+ and CD8+ into tumors and splenocyte proliferation ex vivo, suggesting that the cytokines are important for T cell persistence and proliferation. (See abstract and Fig.5A,B, and F).
Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to combine the teachings of Fidai and Havunen and use an oncolytic adenovirus encoding IL-2 mutein and TNF-α for treating cancer in subject. Because Fidai et al teach a method for the treatment of cancer in a subject comprising administering oncolytic adenoviral vector containing a nucleic acid encoding IL-2 mutein. Havunen et al utilized an oncolytic adenovirus encoding IL2 and TNF-α for treating cancer in a subject. Thus, one would have been motivated to use IL2 mutein- and TNF-α -armed oncolytic adenovirus for treating cancer in a subject, because doing so would improve T cell persistence and proliferation, leading to better antitumor efficacy. Combining prior art elements according to known methods to yield predictable results. See MPEP 2143 (I)(A).
Response to Arguments
Applicant's arguments filed 07/18/2025 have been fully considered but they are not persuasive.
Applicants argue that the cited prior arts each individually disclose a part of components
of the claimed invention, but these references do not suggest the specific combination as claimed in the present application.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the cited references, as discussed in the rejection above, include teachings that are highly relevant and must be weighed in substance. Fidai et al, for example, teach administering to a subject with cancer a therapeutic oncolytic adenoviral vector containing a nucleic acid encoding IL-2 mutein, and further suggest the use of oncolytic vector comprising Ad5-E2F-d24 backbone. Kawakami et al, disclose that the tropism of the oncolytic Ad5 to different types of tumors can be modified by generating a chimeric adenovirus comprising Ad5/3 fiber knob. Liu et al state that “the E1B-19 K deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy”. Bortolanza et al disclose an insertional locus within the adenovirus E3 region that allows therapeutic genes to be incorporated into the backbone of the oncolytic adenovirus without altering the virus’s property. Taken together, it is clearly obvious that claim 21 as a whole is a product of combining prior art elements according to known methods to yield predictable results. A person of ordinary skill in the art who had reviewed Fidai could have come across Kawakami, Bortolanza, and Liu and immediately noticed the strong possibility that use of Ad5/3 vector, the E3 region as an insertional locus, and the deletion of the E1B-19 K gene from the vector backbone, would have predictable results of generating vector with an increased tropism to various types of tumors, as well as enhanced safety, spread, and efficacy, which are especially relevant in gene therapy applications. A person of ordinary skill in the art would see that it is a prima facie obvious to combine these teachings as each is taught by the prior art to be useful for the same purpose of instant application. The idea of combining them flows logically from their having been individually taught in the prior art. Applicant is reminded that when considering the question of obviousness, Office personnel should keep in mind the capabilities of a person of ordinary skill’.
As per the MPEP, (“The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art.”); In re Sneed, 710 F.2d 1544, 1550, 218 USPQ 385, 389 (Fed. Cir. 1983) (“[I]t is not necessary that the inventions of the references be physically combinable to render obvious the invention under review.”); and In re Nievelt, 482 F.2d 965, 179 USPQ 224, 226 (CCPA 1973) (“Combining the teachings of references does not involve an ability to combine their specific structures”).
Additionally, applicants argue that prior art fails to disclose or suggest the unexpected results that the present application demonstrates, such as the levels of vIL-2 polypeptide were high even after 3 days of the last virus-treatment (referring to Fig.10), the deletion of E1B-19K improves the effect of the claimed treatment by enhancing apoptosis of tumor cells infected by the claimed vector, and that the claimed virus is capable of producing high expression of granzymes and perforin inducing tumor cell apoptosis.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/ Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638