Detailed Office 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 .
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 18 September, 2025. Claims 48, 49, and 52-67 are pending in the instant application.
37 C.F.R. § 1.98
The information disclosure statement filed 18 September, 2025, has been placed in the application file and the information referred to therein has been considered.
35 U.S.C. § 112(a)
The following is a quotation 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.
Written Description
Claims 48, 49, and 52-67 stand rejected under 35 U.S.C. § 112(a), 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, at the time the application was filed, had possession of the claimed invention. Amgen, Inc. v. Sanofi, 872 F.3d 1367, 124 U.S.P.Q.2d 1354 (Fed. Cir. 2017). AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 111 U.S.P.Q.2d 1780 (Fed. Cir. 2014). Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 920, 69 U.S.P.Q.2d 1886, (Fed. Cir. 2004). Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316, 63 U.S.P.Q.2d 1609, (Fed. Cir. 2002). Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 U.S.P.Q.2d 1398, (Fed. Cir. 1997). Fiers v. Revel Co., 984 F.2d 1164, 25 U.S.P.Q.2d 1601, (Fed. Cir. 1993). Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016, (Fed. Cir. 1991). In re Rasmussen, 650 F.2d 1212, 211 U.S.P.Q. 323 (C.C.P.A. 1981). In re Wertheim, 541 F.2d 257, 191 U.S.P.Q. 90 (C.C.P.A. 1976).
The crux of the statutory requirement governing written description is whether one skilled in the art, familiar with the practice of the art at the time of the filing date, could reasonably have found the later claimed invention in the specification as filed. In re Kaslow, 707 F.2d 1366, 1375, 217 U.S.P.Q. 1089, 1096 (Fed. Cir. 1983). In re Wilder, 736 F.2d 1516, 1520 222 U.S.P.Q. 349, 372 (Fed. Cir. 1984, cert. denied, 469 U.S. 1209 (1985). Texas Instruments, Inc. v. International Trade Comm’n, 871 F.2d 1054, 1063, 10 U.S.P.Q.2d 1257, 1263 (Fed. Cir. 1989). Moreover, the courts have stated that the evaluation of written description is highly fact-specific, and that broadly articulated rules are inappropriate. In re Wertheim, 541 F.2d 257, 263, 191 U.S.P.Q. 90, 97 (C.C.P.A. 1976). In re Driscoll, 562 F.2d 1245, 1250, 195 U.S.P.Q. 434, 438 (C.C.P.A. 1977). It is also important to remember that the true issue in question is not whether the specification enables one of ordinary skill in the art to make the later claimed invention, but whether or not the disclosure is sufficiently clear that those skilled in the art will conclude that the applicant made the invention having the specific claim limitations. Martin v. Mayer, 823 F2d 500, 505, 3 U.S.P.Q.2d 1333, 1337 (Fed. Cir. 1987).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor has possession of the claimed invention. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 U.S.P.Q.2d 1961, 1966 (Fed. Cir. 1997). The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 U.S.P.Q.2d 1895, 1905 (Fed. Cir. 1996).
Determination of adequate written description requires the Examiner to read and analyze the specification for compliance with 35 U.S.C. § 112(a). In particular, each claim should be analyzed to determine its broadest reasonable interpretation consistent with written description. Each claim should be evaluated to determine if sufficient structures, acts, or functions are recited to make clear the scope and meaning of the claim, including the weight to be given the preamble. The entire application should be reviewed including the specific embodiments, figures, and sequence listings, to understand how applicant provides support for the various features of the claimed invention. The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated that the inventor was in possession of the claimed invention. Such a review is conducted from the standpoint of one of ordinary skill in the art at the time the application was filed (see, e.g., Wang Labs., Inc. v. Toshiba Corp., 993 F.2d 858, 865, 26 USPQ2d 1767, 1774 (Fed. Cir. 1993)) and should include a determination of the field of the invention and the level of skill and knowledge in the art. Finally, the Examiner should determine whether there is sufficient written description to inform a skilled artisan that the inventor was in possession of the claimed invention as a whole at the time of filing.
The claims are directed toward a method of treating cancer comprising administering an oncolytic adenovirus (e.g., EnAd or Ad11) wherein said adenovirus expresses a bispecific T-cell activator (BiTE) comprising at least two binding domains: one specific to CD3 and one specific to a tumour stromal antigen expressed on fibroblasts, tumour-associated macrophages, dendritic cells, NK cells, and/or T-cells which have infiltrated the stroma. The claim breadth encompasses a large genus of tumor stromal antigens which are poorly defined. As Xu et al. (2022) note (see Abstract, p. 1), “the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance.” The authors further note that targeting the tumor stroma has suffered from a number of limitations including a lack of specific cell surface markers on CAFs and TA-MSCs. Zhao et al. (2023) also provide a good review directed toward the role of stromal cells in the tumor microenvironment. It was reported (see left col., p. 1) that to date, “no specific markers have been found in stromal cells” in the tumor-associated stroma.
Furthermore, several obstacles have prevented the utilization of oncolytic adenoviruses as suitable anti-tumor agents. Major obstacles to successful oncolytic therapy include the presence of stroma in tumors, formed by different types of cells and extracellular matrix (ECM) compounds. Stroma not only creates physical barriers that limit oncolytic adenovirus (OAd) spread across the tumor, but also induces tumor progression by enhancing the survival, proliferation, stemness, metastasis, and an immunosuppressive microenvironment that limits tumor immunity, ultimately promoting cancer progression and also enhancing resistance to therapy (Kalluri et al., 2016). Alemany (2014) examined the role of oncolytic adenoviruses in cancer treatment and concluded (see Abstract, p. 36) that “Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses.” Thus, the utilization of oncolytic adenoviruses to treat cancers must overcome several critical obstacles to be successful.
The disclosure only identifies a single putative stromal tumour antigen derived from tumour-associated fibroblasts (fibroblast activation protein-α, or FAP). The disclosure also only provides a single anti-CD3 scFv and a single anti-FAP scFv. No other structures were provided for either target antigens or suitable binding molecules. Guidance pertaining to the CDRs and FRs of other scFv antibody molecules was not provided. Moreover, the disclosure failed to identify any other suitable stromal tumor antigen targets. Thus, the skilled artisan would reasonably conclude that Applicant was not in possession of any additional CD3 or tumor stromal antigen binders.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicant was not in possession of a sufficient number of binding domains to support the full claim breadth currently sought.
Applicant traverses and submits the teachings of Xu et al. (2022) and Zhao et al. (2023) do not preclude the targeting of stromal cells in general. It was argued that the skilled artisan would be able to identify suitable stromal antigens for targeting purposes. Applicants further add that the invention is predicated upon the discovery that oncolytic adenoviruses can selectively infect cancer cells and express the desired BiTE during viral replication. Further arguments suggest that there is no legal requirement that a sufficient number of species need to be provided to support the claimed genus. In any event, the role of the tumour stroma in supporting tumour growth is well-known and the skilled artisan would be capable of identifying suitable stromal antigens and antibody molecules that bind to them.
Applicant’s arguments have been carefully considered but are not deemed to be persuasive for the reasons of record set forth supra. The claims are directed toward a method of treating cancer using the claimed oncolytic adenoviruses. However, in order to practice the claimed invention, the skilled artisan would need to know the stromal antigen target and the precise structure of the scFv expressed by the oncolytic adenovirus. While the Examiner acknowledges that the skilled artisan could readily identify an anti-CD3 scFV, nevertheless, the skilled artisan would still need to know the structure of the stromal antigen/epitope and corresponding scFv, including the attendant CDRs and FRs. As noted supra, the disclosure only describes a single BiTE comprising an anti-CD3 scFv and anti-FAP scFv. No other BiTE molecules were described.
Applicant is reminded that for some biomolecules, possession may be demonstrated by providing examples of identifying characteristics including a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 U.S.P.Q.2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 U.S.P.Q.2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Other ways of establishing possession of a claimed invention may include unique cleavage by particular enzymes, isoelectric points of fragments, detailed restriction enzyme maps, a comparison of enzymatic activities, or antibody cross-reactivity. See Lockwood, 107 F.3d at 1572, 41 U.S.P.Q.2d at 1966 (Stating that the written description requirement may be satisfied by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that fully set forth the claimed invention."). Conversely, describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 U.S.P.Q.2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 U.S.P.Q.2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
When all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicant failed to identify a suitable number of stromal antigens/epitopes and antibody molecules that are capable of binding to them. Amendment of the claim language to identify the stromal target/epitope and incorporate the specific anti-CD3 and anti-FAP scFv utilized in the BiTE would be acceptable.
Enablement
Claims 48, 49, and 52-67 stand rejected under 35 U.S.C. § 112(a), as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The claims are directed toward a method of treating cancer comprising administering an oncolytic adenovirus (e.g., EnAd or Ad11) wherein said adenovirus expresses a bispecific T-cell activator (BiTE) comprising at least two binding domains: one specific to CD3 and one specific to a tumour stromal antigen expressed on fibroblasts, tumour-associated macrophages, dendritic cells, NK cells, and/or T-cells which have infiltrated the stroma.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
1) The claim breadth encompasses a large genus of tumor stromal antigens which are poorly defined. As Xu et al. (2022) note (see Abstract, p. 1), “the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance.” The authors further note that targeting the tumor stroma has suffered from a number of limitations including a lack of specific cell surface markers on CAFs and TA-MSCs. Zhao et al. (2023) also provide a good review directed toward the role of stromal cells in the tumor microenvironment. It was reported (see left col., p. 1) that to date, “no specific markers have been found in stromal cells” in the tumor-associated stroma.
2) The claim breadth encompasses a large genus of CD3 binders and tumour stromal antigen binders. As noted in item 1), tumour stromal antigens can be derived from a number of different sources including cancer-associated fibroblasts, mesenchymal stromal cells, and pericytes. Even if a single tumor antigen is identified, each binding molecule (e.g., an scFv) will have different structures. Antibodies display unique variable heavy (VH) and variable light (VL) chain regions. It has been well-documented that the skilled artisan cannot readily predict the structure of any given antibody for its cognate antigen (Sela-Culang et al., 2013).
3) The disclosure fails to provide adequate guidance with respect to the identification of suitable tumour-specific stromal antigens. Only a single putative tumor antigen was identified, fibroblast activation protein-α, or FAP. No other suitable targets were identified.
4) The disclosure fails to provide adequate guidance with respect to the identification of suitable binding reagents. A single scFc was provided that binds to CD3 and a single scFv was identified that binds to FAP. No other binding reagents were identified.
5) The disclosure fails to provide any working embodiments. While a single anti-CD3 scFv and a single anti-FAP were identified, no other binding reagents were disclosed. Moreover, while these reagents were successfully expressed using a single recombinant oncolytic adenovirus, nevertheless, the specification failed to provide any data from an art-recognized model demonstrating that these reagents were capable of treating any given cancer. Considering the claim breadth, the unpredictability of the art, and the many obstacles associated with the development and utilization of recombinant oncolytic adenoviruses in the treatment of cancer, several working embodiments would be required to enable the claimed invention.
6) The development of efficacious recombinant oncolytic adenoviruses for the treatment of cancer needs still to overcome several obstacles. Alemany (2014) examined the role of oncolytic adenoviruses in cancer treatment and concluded (see Abstract, p. 36) that “Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses.” Thus, the utilization of oncolytic adenoviruses to treat cancers must overcome several critical obstacles to be successful. Several impediments have prevented the utilization of oncolytic adenoviruses as suitable anti-tumor agents. Major obstacles to successful oncolytic therapy include the presence of stroma in tumors, formed by different types of cells and extracellular matrix (ECM) compounds. Stroma not only creates physical barriers that limit oncolytic adenovirus (OAd) spread across the tumor, but also induces tumor progression by enhancing the survival, proliferation, stemness, metastasis, and an immunosuppressive microenvironment that limits tumor immunity, ultimately promoting cancer progression and also enhancing resistance to therapy (Kalluri et al., 2016). Identifying suitable stromal tumour antigens has contributed to this lack of success. As Xu et al. (2022) note (see Abstract, p. 1), “the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance.” The authors further note that targeting the tumor stroma has suffered from a number of limitations including a lack of specific cell surface markers on CAFs and TA-MSCs. Zhao et al. (2023) also provide a good review directed toward the role of stromal cells in the tumor microenvironment. It was reported (see left col., p. 1) that to date, “no specific markers have been found in stromal cells” in the tumor-associated stroma.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that the claimed invention is not enabled.
Applicant traverses and submits the teachings of Xu et al. (2022) and Zhao et al. (2023) do not preclude the targeting of stromal cells in general. It was argued that the skilled artisan would be able to identify suitable stromal antigens for targeting purposes. Applicants further add that the invention is predicated upon the discovery that oncolytic adenoviruses can selectively infect cancer cells and express the desired BiTE during viral replication. In any event, the role of the tumour stroma in supporting tumour growth is well-known and the skilled artisan would be capable of identifying suitable stromal antigens and antibody molecules that bind to them.
Applicant’s arguments have been carefully considered but are not deemed to be persuasive for the reasons of record set forth supra. The claims are directed toward a method of treating cancer using the claimed oncolytic adenoviruses. However, in order to practice the claimed invention, the skilled artisan would need to know the stromal antigen target and the precise structure of the scFv expressed by the oncolytic adenovirus. While the Examiner acknowledges that the skilled artisan could readily identify an anti-CD3 scFV, nevertheless, the skilled artisan would still need to know the structure of the stromal antigen/epitope and corresponding scFv, including the attendant CDRs and FRs. As noted supra, the disclosure only describes a single BiTE comprising an anti-CD3 scFv and anti-FAP scFv. No other BiTE molecules were described. Moreover, Applicant’s response failed to proffer any data from an art-recognized animal model demonstrating that oncolytic adenoviruses expressing an anti-CD3 scFv/anti-FAP scFv BiTE are capable of inhibiting tumour growth and spread.
Action Is Final
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. § 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 extension fee pursuant to 37 C.F.R. § 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.
Correspondence
Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. 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 are unsuccessful, the Examiner's supervisor, Michael Allen, Ph.D., can be reached at (571) 270-3497. Direct general status inquiries to the Technology Center 1600 receptionist at (571) 272-1600.
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Respectfully,
/JEFFREY S PARKIN/Primary Examiner, Art Unit 1671
27 December, 2025