DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment of 7/18/25 has been entered in full. Claims 13-23 are canceled. Claims 1-12 and 24-30 are pending.
Election/Restrictions
Applicants' election without traverse of Group II, claims 1-12 and 24-30, as drawn in the alternative to a method of providing fibroblast therapy by administering fibroblast therapy and an anti-CD3 agent, in the reply filed on 4/3/25 is acknowledged. The elected group reads on each pending claim.
Also acknowledged are Applicants’ elections without traverse of (1) skin as the species of fibroblast source tissue, and (2) anti-CD3 antibody as the species of anti-CD3 agent. Each pending claim reads on the elected species.
Claims 1-12 and 24-30 are under consideration, in so far as directed to the elected invention and species.
Specification
The disclosure is objected to because of the following informalities:
---The title is not descriptive because it is directed to any enhancement of fibroblast therapeutic activity, but the elected invention is limited to use of an anti-CD3 agent for such. A new title is required that is clearly indicative of the claimed invention. The following is suggested: “Enhancement of Fibroblast Therapeutic Activity By T-cell Modulation with an Anti-CD3 Agent”.
---On page 13, line 3, “to activity T cells” should be “to activate T cells”.
Appropriate correction is required.
Claim Objections
Claims 1-12 and 24-30 are objected to for the following informalities:
Claims 1-12 and 24-30 are objected to for reciting the subject matter of inventive groups that were non-elected without traverse. Specifically, these claims recite in the alternative, the subject matter of non-elected Groups I (directed to use of fibroblasts and IL-2) and III (directed to use of fibroblasts, IL-2 and anti-CD3 agent). The subject matter directed to the inventions non-elected without traverse should be removed from the claims under examination.
In each of claims 29 and 30, the term “tolerance inducing” should be hyphenated; i.e., “tolerance-inducing”.
Appropriate correction is required.
Improper Markush Grouping Rejection
Claims 1-12 and 24-30 are rejected on the basis that each contains or encompasses an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the group (i.e., alternatives from which a selection is to be made in the context of a combination or process) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
In independent claim 1, the Markush grouping of (1) interleukin-2 (IL-2) or (2) anti-CD3 agent is improper for the following reasons. First, IL-2 is a protein and does not have activity as an anti-CD3 agent, and an anti-CD3 agent is a genus encompassing multiple compounds with different structures having this activity, and not acting as IL-2, the art does not recognize IL-2 and anti-CD3 agents as belonging to the same class. Second, while IL-2 and anti-CD3 can each be used in the claimed method, they do not share a single structural similarity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 2-12, 27 and 28 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 pre-AIA the applicant regards as the invention.
Claims 2-11, 27 and 28 each recites the limitation “the fibroblasts” in line 1 (claims 2-12), line 2 (claim 27), or line 4 (claim 28). There is insufficient antecedent basis for this limitation in the claim. Specifically, each of these claims depends from independent claim 1, which refers to “a fibroblast therapy” and not “fibroblasts”. The specification does not provide a limiting definition of the term “fibroblast therapy” that renders it equivalent to “fibroblasts”.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 112(a), enablement
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 1-12 and 24-30 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 enablement requirement. The claims contain 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 factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are directed to a method intended to provide a fibroblast therapy to an individual in need thereof, which in view of the elected invention is to be achieved via a single step of providing to the individual an effective amount of the fibroblast therapy and an anti-CD3 agent. The specification teaches that “the disclosure concerns the field of utilizing fibroblasts for a therapeutic purpose, for example to elicit regenerative activities in a subject in need thereof” (¶ 5), and does not provide a limiting definition of the term “fibroblast therapy”, as such this term is broadly interpreted as encompassing any form of therapy with fibroblasts.
The claimed method encompasses use of fibroblasts that are either autologous, i.e., sourced from the same individual to which they are administered; allogeneic, i.e., sourced from a different individual; or xenogeneic, i.e., sourced from a different species. The embodiments directed to autologous, allogeneic or xenogeneic fibroblasts are expressly recited in the alternative in dependent claim 2 and thus are encompassed by independent claim 1 and each of the other claims. The claims further encompass fibroblasts derived from any type of source tissue; dependent claim 4 recites fifteen different types of tissue from which the fibroblasts can be source, with skin fibroblasts being the elected species under consideration. The claims further encompass use of any type of anti-CD3 agent, with dependent claim 24 reciting an antibody, aptamer, siRNA and shRNA as possible types; the elected species under consideration is an anti-CD3 antibody. As such, the claimed method encompasses treatment of any type of disease, condition, or injury with the combination of autologous, allogeneic or xenogeneic fibroblasts of any type, e.g., skin fibroblasts, and an anti-CD3 agent of any type, e.g., an anti-CD3 antibody.
With respect to use of autologous fibroblasts, the specification twice mentions (¶ 7, ¶ 46, published application) that such are alternative embodiment of the claimed method, but does not contain any further teachings specifically mentioning such fibroblasts. In the “Background”, the specification teaches that individuals are “tolerant to the body’s own self-antigens” and that the invention is for “the use of immune modulation to induce acceptance of allogenic fibroblast cell populations possessing therapeutic activities, as well as utilization of immune modulation to augment enhanced therapeutic activities” (¶ 4). The specification further asserts that anti-CD3 agents can “independently trigger production of T regulatory cells that enhance fibroblast regenerative activity” (¶ 6). Thus, with respect to autologous cells, and as directed to the elected species under consideration, the specification appears to assert that the co-administration of autologous skin fibroblasts and an anti-CD3 antibodies will enhance the therapeutic or regenerative activity of said fibroblasts. However, the specification fails to further articulate what exact regenerative activity is possessed by skin fibroblasts, or how exactly the production of regulatory T cells will enhances such activity. Thus, at the time of filing of the instant application, the skilled artisan would not have known, based solely on the teachings of the specification, whether administration of an anti-CD3 antibody would enhance a regenerative property of autologous skin fibroblasts, and would have looked to the instant application to provide predictability that the claimed method would work before using such to treat patients.
With respect to allogeneic or xenogeneic cells, the specification teaches that “the disclosure encompasses methods that overcome some of the limitations surrounding the use of allogeneic fibroblasts by utilizing clinically-tested pharmacological drugs to modulate the immune system in order to accept foreign fibroblasts” (¶ 5) and “to stop allogeneic fibroblasts from being rejected in a recipient individual” (¶ 6). As such, the specification asserts that the purpose of the anti-CD3 agent in the claimed method is to prevent the immune system of the treated subject from rejecting the allogeneic fibroblasts. However, with respect to the use of anti-CD3 agents, the relevant prior art teaches that “studies reveal a narrow therapeutic window of anti-CD3-based therapies in which low doses are ineffective and higher pharmacologically active doses cause intolerable levels of adverse effects” (page 1 of Dean et al, 2012. Swiss Med Wkly. 142: w13711; pages 1-11 as printed). Furthermore, the instant specification itself also teaches that there is unpredictability in the effects of administered anti-CD3 antibodies. Specifically, the specification teaches that “[i]n some situations, antibodies to CD3 cause activation of T cells, not suppression” and that “care that needs to be exercised when manipulating the CD3 pathway, given that the pathway can be both capable of upregulating or inhibitory” cited a prior art teaching (¶ 36). Thus, at the time of filing of the instant application, the skilled artisan would not have known, based solely on the teachings of the prior art and specification, whether administration of an anti-CD3 antibody could overcome the rejection of allogeneic or xenogeneic skin fibroblasts by a recipient, and would have looked to the instant application to provide predictability that the claimed method would work before using such to treat patients.
However, the specification provides extremely limited guidance in support of the method as directed to the claimed invention. There are no working examples or figures showing results provided. Thus, the specification fails to provide any evidence that co-administration of an anti-CD3 antibody will enhance the activity of administered skin fibroblasts when administered for a particular therapy, and further whether an anti-CD3 antibody will prevent the rejection of allogeneic or xenogeneic skin fibroblasts when administered for the same type of therapy. While enablement does not necessarily require a working example, "[l]ack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art", per MPEP 2164.02. In the instant case, it is unpredictable whether administration of an anti-CD3 antibody will function to enhance skin fibroblast activity or prevent rejection of foreign skin fibroblasts. Thus, in order to practice the claimed method, the skilled artisan would first need to engage in experimentation to determine whether administration of an anti-CD3 antibody in conjunction would skin fibroblasts would enhance their activity in any single type of therapy, and then determine whether the anti-CD3 antibody would also prevent rejection when allogeneic or xenogeneic skin fibroblasts were administered for the same type of therapy. The outcome of such a study would generally be the focus of an entire publication in the relevant literature. Such would need to be repeated with a representative range of source tissues for the fibroblasts; the specification envisions at least 14 other types; see dependent claim 4, and with a representative range of anti-CD3 agents, which based on their structure may not function identically to an anti-CD3 antibody. Furthermore, as the claims are unlimited scope with respect to the type of encompassed therapy, such work would need to be repeated with a representative number of other types of therapies in order to support the claimed scope.
Due to the large quantity of experimentation necessary to determine whether or not administration of an anti-CD3 agent, such as an anti-CD3 agent in conjunction with administered fibroblasts, such as skin fibroblasts, can enhance any type of therapeutic activity of the fibroblasts, and further whether administration of an anti-CD3 antibody in conjunction with administered allogeneic or xenogeneic fibroblasts, can overcome the rejection of such fibroblasts by the recipient, the lack of direction/guidance presented in the specification corresponding both the elected species under consideration and to the in scope of the claims as a hole, the lack working examples with respect to field that in which unpredictability is taught by both the specification and the prior art, and the complex nature of the invention, undue experimentation would be required of the skilled artisan to use the claimed invention.
Claim Rejections - 35 USC § 112(a), written description
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 1-12 and 24-30 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The instant claims are directed to a method of fibroblast therapy that, in view of the elected invention, comprises a step of providing fibroblast therapy and one or more “anti-CD3 agents”. The elected species of anti-CD3 agent under consideration is an anti-CD3 antibody. The claims are directed to a method of use of a product rather than a product per se, but practicing said method of use requires a written description of the product to be used in the method; i.e., e.g., the requisite anti-CD3 antibody.
The specification does not provide a definition of the term “anti-CD3 agent”, only providing examples of structures that can have such activity, including antibodies, aptamers, siRNA, and shRNA; see dependent claim 24. The prior art recognizes that “CD3” is not a single protein but a complex of four protein chains, gamma, delta, epsilon and zeta, each of which is encoded by separate gene, and that these associated with the T-cell receptor (TCR) to form the TCR complex and “generate an activation signal in T lymphocytes” (¶ 110 of U.S. Patent Application Publication 20150337049, published 11/26/15). Thus, the term “anti-CD3 agent” broadly encompasses agents that target each of these four chains, both separately or in combination.
Furthermore, the specification does not clearly teach whether “anti-CD3” requires antagonism of CD3 activity or whether the term also encompasses any agent that binds to CD3, whether or not it antagonizes the complex. The inclusion of siRNA and shRNA, which are inhibitory nucleic acid molecules, suggests that the term is directed to agents that antagonize the function of CD3, but the specification indicates that an example of an antibody of the invention is Teplizumab. The specification fails to described Teplizumab further, but the antibody was well known in the prior art. Dean et al (2012) teaches that Teplizumab is a humanized version of “rodent anti-human CD3” mAb and binds to the epsilon chain of CD3 (page 2 of Dean et al, 2012. Swiss Med Wkly. 142: w13711; pages 1-11 as printed).
In the independent claim, the product is only limited by functionality (to being “anti-CD3”) and is not limited structurally, encompassing any possible structure. The specification envisions that these antagonists include at least antibodies, aptamers and nucleic acids, e.g., siRNA and shRNA (as recited in dependent claim 24). Furthermore, the term “agent” broadly encompasses other compounds, such as proteins, lipids, carbohydrates, small organic molecules and inorganic molecules. Each of these, such as the antibodies employed by the elected species under consideration, is a distinct subgenus that encompasses a group of species, each having the required functionality. The genus “antibody” encompasses the full range of monoclonal antibodies, which are each limited to a single defined antibody structure binding to a target antigen. Furthermore, the claims do not require antagonist of CD3 binds to CD3, and thus the subgenus of antibodies that are “anti-CD3” also encompasses antibodies that indirectly affect CD3, i.e., by binding to an upstream regulator.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). As noted above, CD3 is a complex of four protein chains, and these are 182 (gamma), 171 (delta), 207 (epsilon) and 164 (zeta) amino acids in length (¶ 110 of U.S. Patent Application Publication 20150337049, published 11/26/15). Thus, even considering only continuous epitopes, the epsilon chain (for example) comprises a multitude of different regions of five amino acids that can serve as epitopes (e.g., residues 1-5, 2-6, 3-7, up to residues 202-207). While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure of other antibodies that bind to the same epitope or to the other epitopes in the same protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36). Thus, there are at least hundreds of different antibody structures that bind to each of the four chains of the CD3 protein. Furthermore, as noted above, the elected invention under consideration also encompass antibodies that are indirect (i.e., upstream) “anti-CD3” agents.
Thus, the claims are genus claims because they encompass use of a genus of antibodies having the required functionality, i.e., binding to CD3. However, a product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function; i.e., the structure of one anti-CD3 antibody does not provide predictability regarding other antibody structures having the same functionality. Furthermore, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g. one of the CD3 protein chains) is not in and of itself sufficient to provide a description of the genus of antibodies binding to said target.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
In support of the genus of anti-CD3 antibodies, the specification does not provide any examples other than that of Teplizumab, which binds to the epsilon chain. A description of a single monoclonal antibody that is defined by its amino acid sequences is not representative of a genus of monoclonal antibodies with hundreds or more members having different structures. Per MPEP 2163, "A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
With respect to the broader genus of “anti-CD3 agent”, the specification further does not provide examples of a range of other, non-antibody structures corresponding to this functionality, i.e., aptamers and nucleic acids. Thus, the specification also does not provide representative number of species of the genus of “anti-CD3 agent” to be used in the claimed method.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only a method of providing a fibroblast therapy to an individual in need thereof, comprising the step of providing to the individual an effective amount of the fibroblast therapy and an anti-CD3 agent that is Teplizumab, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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) Form at https://www.uspto.gov/patents/uspto-automated-interview-request-air-form.
/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674