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 .
Status of the Claims
Claims 1-8 and 12-14 are currently pending.
Claim 1 is amended.
Claims 9-11 are cancelled.
Claims 1-8 and 12-14 have been considered on the merits.
Withdrawn Rejections
The 112(a) rejection made onto claim 1-8 and 12-14 is withdrawn in light of the amendments and arguments submitted on 12/16/2025.
New Rejections
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 1-8 and 12-14 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:
A method of treating hepatocellular carcinoma, comprising:
intravenously administering to a human subject in need thereof, a human T cell, wherein the human T cell comprises:
a) a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain specific for Glypican-3 (GPC3), and
b) an armoring molecule,
wherein the antigen-binding domain comprises a scFv comprising a heavy chain variable region (VH) and a light chain variable region (VL),
wherein the VH comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 37, a CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 39, and wherein the VL comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 42,
wherein the armoring molecule is a dominant-negative TGF-(3 receptor type 2 (TGFPRIIDN) comprising amino acids 477 to 671 of SEQ ID NO: 47,
wherein the hepatocellular carcinoma is GPC3 positive.
The specification does not reasonably provide enablement for the method of treating hepatocellular carcinoma employing any cell type and administered through any route of administration. 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 and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims broadly encompass a method of treating hepatocellular carcinoma in a subject in need thereof, comprising the steps of administering a cell to a subject, wherein the cell contains a CAR and an armoring molecule. Thus, the claims taken together with the specification imply that any cell type and any route of administration can be employed in the instantly claimed method.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The claims embody a method of treating hepatocellular carcinoma through the administration of any cell containing a CAR and armoring molecule to a human experiencing hepatocellular carcinoma through any route of administration, which is unpredictable.
This method is found to be unpredictable with regards to treating hepatocellular carcinoma through the use of any cell type and through any route of administration.
Regarding the use of any cell type in the method of treating hepatocellular carcinoma, the use of any cell other than a human T cell is found to be unpredictable. Additionally, the use of a xenogeneic cell is found to be unpredictable.
Qin et al (Cancers, 2021) teaches a review of the use of chimeric antigen receptors on immune cells. Qin teaches that “the majority of research interest in CAR technology has been focused on CAR-T cells to date” (abstract). Qin describes the state of the art at the time of publishing and provides numerous examples of immune cells which have been employed for CAR cell therapies (Table 1). Qin describes that in the last 20 years CAR technologies have been developed for other immune cell subsets, however T lymphocytes remain the most common cell type employed (pg. 10, para 1). Additionally, Qin states in reference to the use of CAR-immune cells in the alternative to CAR-T cells that “Further studies will be needed to explore the anti-tumour efficacy, as well as safety, of these CAR-engineered immune cells” (pg. 11, para 2). Qin is demonstrating that in the field of CAR cell therapies, the predictable use of CAR cells is through the use of T cells, in the engineering of a CAR cell. Additionally, the use of any cell, other than T cells, for the CAR cell would require undue experimentation. Therefore, without explicit guidance provided by the instant disclosure it would be unpredictable to employ any other cell besides an immune cell as the CAR cell of the instant method.
Li et al (Med, 2025) teaches a review on CAR cell therapy employing human autologous or allogeneic cells (abstract). Li states “[c]ompared with FDA-approved autologous CAR-T cell therapies, allogeneic CAR cell therapies have yet to achieve comparable clinical efficacy” (pg. 14, col. 2, last para). Li is exemplifying that autologous CAR-T cell therapies are currently the most well characterized and FDA-approved CAR-T cell therapy. Li also discloses that allogeneic therapies would allow advantages for “off-the-shelf” availability, lower costs, and allows for scalable production (Fig. 1). Although these advantages exist, they are most concerned with clinically availability and cost. The disadvantages of allogeneic are a risk of immune rejections, shorter persistence of the cells in the body due to immune clearance, and the cells require genetic modification to reduce immune rejection risk (Fig. 1). These disadvantages are directly related to the function of the cells when employed in CAR cell treatments. However, Li provides 5 categories of allogeneic CAR cell therapies that have been successfully implemented in clinical trials, demonstrating promising anti-tumor efficacy and safety (Fig. 3). Therefore, Li demonstrates that the state of the art in human clinical trial CAR cell therapies is administration of either autologous or allogeneic human CAR cells. Therefore, without direct guidance from the instant disclosure on how to perform the method of treatment with non-human CAR cells (i.e. xenogeneic cells), the method remains unpredictable.
Regarding the treatment method employing any route of administration, this is found to be unpredictable. Wang et al (Liver International, 2025) teaches about functionality of anti-GPC3 CAR-T cells against hepatocellular carcinoma (HCC) in reference to the route of administration. Generally, the most common CAR cell administration route is intravenous administration. Wang teaches that “recent CAR-T clinical trials for HCC treatment yielded unsatisfactory outcomes, which however, only tested the traditional intravenous infusion for CAR-T cell delivery” (pg. 2, col. 2, para 1). Additionally, Wang states that “phase I clinical trials using traditional systemic delivery of GPC3 CAR-T cells reported a relatively low response rate among patients, with a partial response rate of <20%” (pg. 2, col. 1, para 2). Therefore, Wang exemplifies that any route of administration will not result in the effective treatment of the cancer. Wang teaches that injections via the portal vein exhibited superior tumor inhibition compared to intravenous (tail vein injection). Therefore, Wang demonstrates that without guidance from the instant disclosure on how to administer the treatment, the treatment remains unpredictable.
Due to the unpredictable nature of employing any cell type in the CAR cell treatment method through any route of administration, the only predictable application of the instant method of treating hepatocellular carcinoma would be through the use of human CAR-T cells, administered intravenously.
(4) The relative skill of those in the art:
The relative skill of those in the art is high.
(5) The amount of direction or guidance presented and (6) the presence or absence of working examples:
The specification details examples 1-5, (including two labeled Example 3 which are denoted with pg. numbers below). Examples 1 and 2 detail TGFB gene expression and signaling in liver hepatocellular carcinoma. Example 3 (pg. 27) details the armoring of GPC3 CAR-T cells with TGFBRIIDN. Example 3 (pg. 29) details the TGFBRIIDN armored CAR-T cell cytotoxicity and expansion during co-culture with GPC3+ cells. Example 4 details the TGFBRIIDN armored CAR-T cells in a in vivo xenograft model. Example 5 details TGFBRIIDN armored CAR-T cells in vivo in a hepatocellular carcinoma patient-derived xenograft model. Therefore, the specification’s only working examples are those which are optimized for use in mice, and the method remains unpredictable in relation to use in humans.
(7) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
It is the examiner’s position that one skilled in the art could not practice the invention commensurate in the breadth of the claims without undue experimentation. Therefore, claim 1 and its dependents are rejected under 35 U.S.C. 112, first paragraph, for a lack of scope of enablement.
Response to Arguments
Applicant’s arguments, see Remarks, filed 12/16/2025, with respect to the rejection(s) of claim(s) 1-8 and 12-14 under 35 USC 112(a) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made under 35 USC 112(a).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632