DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Receipt is acknowledged of the amendments and arguments filed on 27 April, 2026.
Applicant previously elected the species of “modified lymphocytes and/or tumor infiltrating lymphocytes further comprising a recombinant hyaluronidase” without traverse.
Claims 69, 73-74, 83-84, and 88 are amended. Claim 71 is cancelled. Claim 89 is newly added.
Therefore, claims 69-70, and 72-89 are pending and under examination in the present Official Action. Claims 69 and 87 are independent claims.
Priority
The present application is (1) a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/049259, filed 31 August, 2020, which claims priority to United States Provisional Application Nos. 62/985,741, 62/943,207, 62/894,926, 62/894,852, 62/894,853, and 62/894,849 filed 05 March, 2020, 03 December, 2019, 02 September, 2019, 01 September, 2019, 01 September, 2019, and 01 September, 2019 respectively, and (2) a continuation-in-part of International Application No. PCT/US2019/049259 filed 02 September, 2019. Acknowledgement is made of Applicant’s claim for priority.
Therefore, the earliest possible priority for the instant application is 01 September, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 14 April, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
The objection to claim 83 because it lacks a definite article (e.g. “the”) before “cell formulation” is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 83 to recite “the” in the appropriate location.
Maintained Rejections in view of Applicant’s Amendments and Arguments
Claim Rejections - 35 USC § 112
The rejection of claims 69-87 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn over claims 69-74, and 81-88, and maintained over claims 75-80 and newly applied to new claim 89 in view of Applicant’s amendments and arguments.
Applicant has amended the claims to correct previously rejected issues of indefiniteness in claims 69-74, and 81-88. With regard to Applicant’s usage of “and/or” in the claims, Applicant had argued that each recitation covers either of the limitations individually as well as combinations of both for each place where “and/or” is used. This argument has been found persuasive and the indefiniteness rejection for using “and/or” has been withdrawn accordingly.
Claim 75 remains indefinite in its recitation of “the modified lymphocytes are associated with a replication incompetent recombinant retroviral particle” as it is unclear as to the association or associations that are intended as being encompassed by the noted phrase. Modified lymphocytes are known in the prior art to have numerous associations, both specific and general. For example, lymphocytes can be transfected with a replication incompetent recombinant retroviral encoding a gene of interest. It is suggested that applicant clarify the intended meaning of the noted phrase. Claims 76-80 and new claim 89 are further rejected for their dependency on a rejected base claim.
Response to Traversal
Applicant argues that the instant specification states “a modified cell associates with a replication incompetent recombinant retroviral particle through interactions between proteins on the surface of the cell and proteins on the surface of the replication incompetent retroviral particle” and that this recitation in the supporting disclosure renders the scope of claim 75 clear (Remarks, page 6). This argument has been fully considered but has not been found persuasive for the following reasons.
Applicant is reminded that in determining whether the claims satisfy the requirement set forth under § 112(b), M.P.E.P. § 2106 (II) states:
USPTO personnel are to give claims their broadest reasonable interpretation in light of the supporting disclosure. In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997). Limitations appearing in the specification but not recited in the claim should not be read into the claim. E-Pass Techs., Inc. v. 3Com Corp., 343 F.3d 1364, 1369, 67 USPQ2d 1947, 1950 (Fed. Cir. 2003) (claims must be interpreted “in view of the specification” without importing limitations from the specification into the claims unnecessarily). In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 551 (CCPA 1969). See also In re Zletz, 893 F.2d 319, 321-22, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989) (“During patent examination the pending claims must be interpreted as broadly as their terms reasonably allow.... The reason is simply that during patent prosecution when claims can be amended, ambiguities should be recognized, scope and breadth of language explored, and clarification imposed.... An essential purpose of patent examination is to fashion claims that are precise, clear, correct, and unambiguous. Only in this way can uncertainties of claim scope be removed, as much as possible, during the administrative process.”).
The use of “associated with” in claim 75 is ambiguous insofar as it is unclear whether the viral particles are intended to be bound to the cell surface, implanted into the membranes of the cells, internalized within the cells, or some other “association” which falls within the scope of claim 75. The cited terminology from the Specification makes clear that it is an association between proteins on the cell surface and proteins on the surface of the viral particle. However, the claim must only be read in light of the specification and these limitations cannot be read into the claim as to do so would directly import positive claim limitations from the specification (surface protein interaction). Accordingly, this argument has been fully considered but has not been found persuasive.
Claim Rejections - 35 USC § 103
Claims 69-70, and 72-88 remain rejected and new claim 89 is newly rejected under 35 U.S.C. 103 as being unpatentable over WO2018/009923 (Published: 11 January, 2018) (hereinafter “Frost”) (Of Record) in view of US2010/0143457 (Published: 10 June, 2010) (hereinafter “Wei”), WO2019/165097 (Published: 29 August, 2019) (hereinafter “Ang”) (Of Record), WO2017/177149 (Published: 12 October, 2017) (hereinafter “Low”), Li et al. Autoimmunity 52.3 (2019): 102-107. (published: 25 June, 2019) (hereinafter “Li”) (Of Record), and Kleiveland et al. Peripheral Blood Mononuclear Cells. The Impact of Food Bioactives on Health: in vitro and ex vivo models [Internet]. Cham (CH): Springer; 2015. Chapter 15. (hereinafter “Klieveland”). This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Regarding claim 69, Frost discloses methods and compositions for genetically modifying T cells and/or NK cells (lymphocytes) with replication incompetent recombinant retroviruses, T cell and/or NK cell products of these methods, and methods of using such cells as an adoptive cell therapy (Frost, Abstract). Frost teaches modifying T cells to produce CAR T cells and their use for treating tumors (Frost, Abstract, [0005], [0429]).
Frost does not teach recombinant hyaluronidase at a concentration between 50 and 5,000 units/ml or formulating the cells for subcutaneous administration (intended use).
Wei teaches soluble PH20 polypeptides, teaches that PH20 polypeptides are human hyaluronidases, and teaches that hyaluronidases increase tissue permeability and increases the dispersion and delivery of therapeutic agents (Wei, [0006]-[0008]). Wei also teaches that PH20 is useful for treating tumors (Wei, [0017]) and can be administered subcutaneously (Wei, [0333]). Wei also teaches that therapeutically effective doses for soluble PH20 polypeptides range between 10 to 500,000 units and can be in a total volume of 1ml (Wei, [0261]). Therefore, a person having ordinary skill in the art would have been motivated by the teachings of Wang to include PH20 in a therapeutic composition for treating tumors and Wei suggests to a person having ordinary skill in the art to use a concentration of between 10 and 500,000 units/mL.
The combined teachings of Frost and Wei do not disclose a cell formulation for subcutaneous administration.
Ang teaches the subcutaneous administration of T cells or NK cells expressing a CAR (Ang, [0016], [0021], [00104]). Ang also teaches that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer (Ang, [00107]). Therefore, a person having ordinary skill in the art would have been motivated by the teachings of Ang to administer T cells or NK cells expressing a CAR subcutaneously depending on the cancer being treated.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have formulated the T cells and/or NK cells of Frost for subcutaneous administration as taught by Ang and to have included PH20 at a concentration between 10 and 500,000 units/ml as taught by Wei in said formulation to arrive at the invention claimed in instant claim 69 with a reasonable expectation of success because they would have been motivated to do so to achieve particular therapeutic effects depending on the cancer being treated and to increases the dispersion and delivery of therapeutic agents respectively. There would have been a reasonable expectation of success in combining Frost, Wei, and Ang because the T cells and/or NK cells of Frost could readily be formulated for subcutaneous administration and adding PH20 as taught by Wei would reasonably be expected to increase the therapeutic effects of the cells.
Regarding claim 70, Frost teaches infusing 7 x 106 transduced cells to a 70 kg subject (Frost, [0131]). Frost does not explicitly teach a volume of 2 to 1,000mL.
However, Low teaches methods of treating patients with cancer by administering a composition comprising CAR T cells (Low, Abstract). Low teaches that suitable volumes for the cell compositions range from about 5mL to about 200mL containing 1 x 105 to about 1 x 1015 transduced CAR T cells (Low, page 38, lines 3-14).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used a composition volume of at least about 5mL to about 200mL as taught by Low in the methods of Frost and to have arrived at the invention claimed in instant claim 70 with a reasonable expectation of success because they would have been motivated to do so by Low’s teaching of the suitability of said volumes for cell therapy. It is noted that instant claim 70 is directed to a composition and not a method of treatment. A person having ordinary skill in the art would understand that larger volumes than those stated in Low would be advantageous for multiple administrations of the about 5mL to about 200mL as taught by Low. Hence, the Examiner’s use of “at least” in the above rejection.
Regarding claim 72, Wei teaches PH20.
Regarding claim 73, Frost teaches wherein at least 10, 20, or 25% of the T cells are transduced, thereby producing genetically modified T cells (Frost, [0483]).
Regarding claim 74, Frost teaches isolating T cells (lymphocytes) from peripheral blood (PBMCs) and modifying them via retroviral transduction (Frost, [0482]-[0484]).
Regarding claim 75, the T cells (lymphocytes) are contacted with a replication incompetent retroviral particle which comprises a polynucleotide and the polynucleotide comprises one or more transcriptional units operatively linked to a promoter active in T cells and wherein the polynucleotide further encodes a polypeptide (Frost, [0482]-[0485]). “associated with” as used in claim 75 is interpreted as encompassing “contact” as used in Frost.
Regarding claim 76, the polypeptide is a chimeric antigen receptor (CAR) (Frost, [0485]).
Regarding claim 77, the retrovirus comprises an activation element on its surface (Frost, [0485]).
Regarding claim 78, the retroviral particle of Frost is a lentiviral particle (Frost, [0489]).
Regarding claim 79, at least 80% of the transduced cells of Frost do not express the polypeptide because Frost teaches that about 5% do express said polypeptide (Frost, FIG. 23A, [0033]).
Regarding claim 80, Frost teaches that the T cells integrate the polynucleotide into their genome (Frost, [0583]). Frost also teaches wherein at least 10, 20, or 25% of the T cells are transduced, thereby producing genetically modified T cells (Frost, [0483]). Therefore, Frost teaches wherein at least 75% of the modified lymphocytes do not have the polynucleotide stably integrated into their genomes.
Regarding claim 81, Frost, Wei, Ang and Low do not teach at least 10% of the cells in the formulation form aggregates of T cells and/or NK cells that are at least 15μm in their smallest dimension.
Li teaches that activated T cells grow in clusters and that, with daily disaggregation via pipette mixing, the clusters can reach 2μm in diameter or 250μm in diameter (Li, page 4, paragraph 2). Li provides micrographs which depict the majority of cells as being part of the clusters (reading on “at least 10%” of the cells) (Li, fig. 1). Frost teaches that the T cells can be activated (Frost, [0004]-[0005]) and that the retroviral particles comprise an activation element capable of binding to and activating T cells (Frost, [0011], FIG. 1).
Therefore, a person having ordinary skill in the art would have understood from the teachings of Li and Frost that the activated T cells of Frost form clusters necessarily by nature of them being activated T cells. It would have been prima facie obvious to a person having ordinary skill in the art to have had at least 10% of the T cells in the formulation of Frost form cell aggregates of at least 15μm diameter and to have arrived at the invention claimed in instant claim 81 because they would have been motivated to do so because Li teaches that activated T cells naturally form clusters fitting these characteristics and Frost teaches to activate the T cells. Further, there would have been a reasonable expectation of success insofar as activating T cells with a retroviral particle comprising an activating element as taught by Frost would reasonably result in the formation of T cell aggregates.
Regarding claim 82, Frost teaches infusing 7 x 106 transduced cells to a 70 kg subject (Frost, [0131]), and Low teaches that suitable volumes for the cell compositions range from about 5mL to about 200mL containing 1 x 105 to about 1 x 1015 transduced CAR T cells (Low, page 38, lines 3-14).
Regarding claim 83, Wei teaches devices for delivery (Wei, [0101],[0254]), and teaches injection devices such as a needle so as to facilitate administration (e.g. sub-epidermal administration) (Wei, [0233], [0265]).
Regarding claim 84, Frost, Wei, Low, Ang, and Li are silent as to viability.
However, viable cell counting is well within the level of ordinary skill in the art for cell therapies (See for example Frost, [0684]), and the methods and compositions utilizing CAR T cells of Frost, Low, Ang, and Li are taught in the context of cell therapy. A person having ordinary skill in the art would readily understand that maximizing the number of viable cells in a therapeutic composition is desirable for maximizing the therapeutic effects of said composition and it is well within the level of ordinary skill in the art to count and select for viable cells in a cell composition to approach viable cell percentages of at least 60%.
Regarding claim 85, Low teaches infusible CAR-expressing cytotoxic T lymphocyte compositions comprising albumin and DMSO (Low, page 37, lines 20-33).
Low does not teach precise amounts for the albumin or the DMSO beyond stating “2% human serum albumin.” It is noted that, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). In this case, Low teaches the general conditions of an infusible composition comprising CAR T cells, and the level of ordinary skill in the art for cell therapeutics encompasses the variation of infusion components to optimize therapeutic effects. Thus, it is not inventive to discover the optimal range of albumin and DMSO by routine experimentation. Regarding the pH, Frost teaches the co-administration of pH-modulating agents with CAR T-cells and teaches tumor microenvironment-restricted CARs that are more active at lower pH levels of 5.8-7.0 and less active at physiological pH levels of 7.2-7.8 (Frost, Abstract, [0432], [0437]). Ang teaches that the pH of a pharmaceutical composition comprising CAR T cells can be adjusted according to well-known parameters (Ang, 0047]). Thus, the CAR T cells of Frost and Ang are taught as being able to be formulated at a pH range spanning 5.8-7.8 which encompasses well known physiological levels.
Regarding claim 86, Ang teaches that any and all aqueous solvents, non-aqueous solvents, isotonic agents and other component categories may be used as a pharmaceutically acceptable carrier and teaches sodium chloride as one such example (Ang, [0047]). Wei teaches adding potassium chloride to an infusion fluid (Wei, [0328]), teaches pharmaceutically acceptable compositions comprising magnesium carbonate, and “other such agents” (Wei, [0229]), and teaches sodium acetate (Wei, [0236]). Low teaches adding gluconate salts to the CAR T cell compositions (Low, page 32, lines 5-12). A person having ordinary skill in the art would understand magnesium chloride to fall within the “other such agents” taught by Wei and would understand sodium gluconate to be the salt of gluconate. Thus, the combined teachings of Ang, Wei, and Low render obvious a formulation further comprising sodium chloride, potassium chloride, sodium acetate, sodium gluconate, and magnesium chloride.
Regarding claim 87, Frost teaches a method of treating a disease comprising introducing an expression vector comprising a polynucleotide sequence encoding a CAR to peripheral blood cells obtained from the subject to produce genetically engineered cytotoxic cells, and administering said cells to a subject (Frost, [0476]). Frost also teaches contacting resting T cells and/or NK cells with replication-incompetent retroviral particles comprising a polynucleotide encoding one or more transcriptional units to produce genetically modified T cells and/or NK cells and administering said cells to a subject (Frost, [0479]). Frost also teaches that the T cells integrate the polynucleotide into their genome (Frost, [0583]). Frost also teaches wherein at least 10, 20, or 25% of the T cells are transduced, thereby producing genetically modified T cells (Frost, [0483]). Therefore, Frost teaches wherein at least 25% of the modified lymphocytes do not have the polynucleotide stably integrated into their genomes.
Frost does not teach subcutaneous administration or the specific step of collecting the cells to form a cell formulation. However, a person having ordinary skill in the art would understand that, following viral transduction, engineered T cells would need to be placed in a device for the administration of Frost to occur. Placing cells in a device for administration is encompassed by the broadest reasonable interpretation of “collecting”.
Ang teaches the subcutaneous administration of T cells or NK cells expressing a CAR (Ang, [0016], [0021], [00104]). Ang also teaches that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer (Ang, [00107]). Therefore, a person having ordinary skill in the art would have been motivated by the teachings of Ang to administer T cells or NK cells expressing a CAR subcutaneously depending on the cancer being treated.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have administered the T cells and/or NK cells of Frost subcutaneously as taught by to arrive at the invention claimed in instant claim 87 with a reasonable expectation of success because they would have been motivated to do so to achieve particular therapeutic effects depending on the cancer being treated. There would have been a reasonable expectation of success in combining Frost, and Ang because the T cells and/or NK cells of Frost could readily be formulated for subcutaneous administration.
Regarding claim 88, Frost teaches that immune cells comprises T cells as well as monocytes and teaches that the method does not include a step of removing monocytes (Frost, [0057], [0099], [0695]). The peripheral blood cells obtained from the subject in Frost necessarily comprise T cells and/or NK cells since the peripheral blood is the starting material and the method proceeds to contact T cells and/or NK cells from the peripheral blood. Klieveland teaches that PBMCs include 10-20% monocytes generally (Klieveland, page 162, first paragraph). Thus, a person having ordinary skill in the art would have understood the modified cells of Frost to include 10% monocytes as in claim 88.
Regarding claim 89, Frost teaches an anti-CD3 antibody as the activation element on the replication incompetent recombinant retroviral particle (Frost, [0505]-[0507]).
Response to Traversal
Applicant argues against the prima facie obviousness of the instant invention by arguing (1) Wei teaches away from the claimed invention; (2) a skilled artisan would not have been motivated to combine the references; (3) a skilled artisan would not arrive at the claimed invention by combining Frost with Kleiveland; (4) the motivations to combine are based on hindsight; (5) there is no reasonable expectation of success in the combination of Frost and Wei; (6) there is no reasonable expectation of success in the combination of Frost and Li; and (7) unexpected results demonstrate that the administration of modified T cells subcutaneously is non-obvious (Remarks, page 7). These arguments have been fully considered but have not been found persuasive for the following reasons.
(1) Applicant argues “Wei does in fact disclose using hyaluronidases "to increase the dispersion and delivery of therapeutic agents" and "as dispersing and spreading agents in combination with other therapeutic agents." (para. [0006], emphasis added). Notably, the therapeutic agents disclosed in Wei do not include cells. (see, e.g., para. [0089]: "As used herein, a therapeutic agent, includes any pharmaceutically effective agent or bioactive agent, including, but not limited to, for example, anesthetics, vasoconstrictors, dispersing agents, conventional therapeutic drugs, including small molecule drugs, including, but not limited to, bisphosphonates, and therapeutic proteins, including, but not limited to, insulin, IgG molecules, and antibodies."; and para. [0015]-[0016]). Furthermore, Wei explicitly teaches that hyaluronidase would not be used as to increase the dispersion and delivery of cells as the pores generated by hyaluronidase would not "promote the dislocation and movement of cells". (para. [0330]: "The channels opened following administration of hyaluronidase are of a size that typically enhance diffusion of smaller molecules such as retroviruses, adenoviruses, adeno-associated viruses and DNA complexes (as well as other therapeutic and pharmacological agents of interest). The pores are not so large, however, as to promote the dislocation and movement of cells."” (Remarks, page 7-8).
While it is true that Wei contains the cited language that Applicant has pointed to, this falls short of a teaching away from the use of a recombinant hyaluronidase in the present combination of references because, as Ang points out in the same paragraph cited in the instant rejection, the T cells or NK cells engineered to express a CAR “can be used alone or in combination with other well-established agents useful for treating cancer” (Ang, [00107]). These agents can be an immunomodulatory agent, a monoclonal antibody, or a chemotherapeutic agent (Ang, [00110]). Thus, when combining the teachings of Frost, Ang, and Wei, a person having ordinary skill in the art would not have been discouraged from including recombinant hyaluronidase in a cell therapy comprising T cells or NK cells engineered to express a CAR and formulated for subcutaneous administration because Ang teaches that, in this context, the addition of additional therapeutic agents which would benefit from the increased cell porosity provided by the hyaluronidase would be routine. In seizing on the teaching that hyaluronidase can facilitate entry of only limited sizes of molecules into cells, Applicant has ignored the fact that the instant rejection is based upon the combination of Frost, Ang, and Wei, and not simply on Frost and Wei. When viewing Frost, Ang, and Wei together, a person having ordinary skill in the art would not be discouraged from adding a hyaluronidase into a subcutaneous formulation of engineered T cells or NK cells. Accordingly, this argument has been fully considered but has not been found to be persuasive.
(2) Applicant argues, “As discussed above, Wei teaches away from combining hyaluronidase with cells, and thus a skilled artisan would not be motivated to combine Wei with Frost. A skilled artisan would not be motivated to combine Wei with Frost for an additional reason. The Office Action states that "Wei also teaches that PH20 is useful for treating tumors". (Office Action, p. 9). However, Wei teaches that PH20 is useful for treating cancers/tumors for either its "direct anticarcinogenic effects by degradation of hyaluronic acid in tumors" (Wei, [0306]) or "to increase the sensitivity of tumors that are resistant to conventional chemotherapy." (Wei, [0308]). For either of these uses with cancers/tumors, Wei provides the formulation with hyaluronidase "can be injected intratumorally with anti-cancer agents or intravenously for disseminated cancers or hard to reach tumors." (Wei, [0309]). Such a formulation from Wei would not be administered subcutaneously, as recited in the pending claims, because it would not have the desired effect of degrading hyaluronic acid in tumors or increasing sensitivity of chemoresistant tumors. In this section of Wei teaching the use of hyaluronidase in cancer treatment, it discloses that the anti-cancer agent in such a formulation "can be a chemotherapeutic, an antibody, a peptide, or a genetherapy vector, virus or DNA.", i.e., not cells. (Wei, [0309]). Thus, a skilled artisan reading Wei would not be motivated to combine the hyaluronidase of Wei, which teaches the intratumoral or intravenous administration for cancer/tumor treatment with the modified cells of Frost” (Remarks, page 8). Applicant continues with an attack on Ang, Low, and Li in their individual capacities without addressing the prior art of record as a whole.
As discussed above, Wei does not teach away from including hyaluronidase in an engineered T cell or NK cell formulation for subcutaneous administration when considered alongside Frost and Ang together. Further, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, Applicant has presented arguments against a motivation to combine the references by attacking Wei, Ang, Low, and Li individually. Wei teaches that hyaluronidases increase tissue permeability and increases the dispersion and delivery of therapeutic agents, and Ang teaches that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer. Thus, Wei and Ang both provide respective motivations to combine their teachings with Frost who teaches methods of producing CAR cell therapies by providing a motivation to use subcutaneous administration of CAR cell therapies to treat tumors and an additional additive which can increase the therapeutic efficacy of such a subcutaneous cell therapy. In response to Applicant’s argument against Low that a volume above 2ml would cause pain and discomfort, Applicant is reminded that Applicant is currently claiming a range of 2 to 1000ml. In response to Applicant’s argument against Li that Li is focused on a different area than Frost, this argument is immaterial to the thrust of the instant rejection. Li simply teaches that activated T cells grow in clusters and Frost teaches that the T cells are activated. Therefore, a person having ordinary skill in the art would have reasonably expected the activated T cells of Frost to have been present in clusters. This is an inherent property of activated T cells as taught by Li who also teaches that the size and amount of these clusters can be modified with simple pipetting. Accordingly, these arguments have been fully considered but have not been found persuasive.
(3) Applicant argues “The Office Action states Kleiveland "teaches that PBMCs include 10-20% monocytes generally". (Office Action, p. 16). However, Kleiveland simply teaches the typical percentages of various cell types in PBMCs. In contrast, pending claim 88 recites "wherein at least 10% of the monocytes present in the blood sample are present in the cell formulation". This claim is not reciting that at least 10% of the cells in the blood sample are monocytes, as taught in Kleiveland. Instead, it is reciting that at least 10% of the monocytes from the blood sample remain in the cell formulation. Typically, methods including contacting T cells and/or NK cells with replication incompetent recombinant retroviral particles include a step of purifying or enriching certain cell types. Claim 88 recites that even if there is some purification or enrichment, at least 10% of the monocytes from the blood sample remain in the cell formulation. For example, if there were 100 monocytes in the blood sample, then the cell formulation will have at least 10 monocytes. Thus, a skilled artisan would not arrive at the claimed invention by combining Frost with Kleiveland” (Remarks, page 10-11).
Frost teaches that immune cells comprises T cells as well as monocytes and teaches that the method does not include a step of removing monocytes (Frost, [0057], [0099], [0695]). The peripheral blood cells obtained from the subject in Frost necessarily comprise T cells and/or NK cells since the peripheral blood is the starting material and the method proceeds to contact T cells and/or NK cells from the peripheral blood. Klieveland teaches that PBMCs include 10-20% monocytes generally (Klieveland, page 162, first paragraph). Thus, a person having ordinary skill in the art would have understood the modified cells of Frost to include 10% monocytes as in claim 88. This portion of the instant rejection relies on an inherent property of PBMCs as evidenced by Klieveland coupled with there being no mention of a depletion step in the method of Frost. The example provided by Applicant inexplicably asserts a purification step that reduces monocytes from “100” to “10”. No such step is claimed, and no such reduction is shown in the instant invention. Accordingly, this argument has been fully considered but is not found to be persuasive.
(4) Applicant argues “The Office Action fails to consider the claims as a whole and instead relies on impermissible hindsight reconstruction, using Applicant's disclosure as a roadmap to supply both the structure of the claimed invention and the alleged motivation to combine the cited references. At the time of filing of the instant application, cell formulations were predominantly administered intravenously and were not combined with hyaluronidase, and a skilled artisan would therefore have had no motivation to combine Frost with Wei and Ang absent hindsight. Likewise, Low has no specific teaching about administering large volumes subcutaneously and Li specifically teaches that aggregates are detrimental, providing no motivation to combine the references, and Kleiveland does not provide the recited element of claim 88. Thus, the Office Action improperly relies on the instant claims as the rationale for combining the cited references” (Remarks, page 11).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Here, Applicant is just summarily announcing that these claims could only be obvious if impermissible hindsight were used with a reiteration of the same arguments made above regarding the references individually. The above rejection takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure. Accordingly, the rejection is proper and this argument has been fully considered but has not been found persuasive.
(5) Applicant argues “Even assuming there was a motivation to combine the cited references as proposed in the Office Action, a skilled artisan would not have had a reasonable expectation of success to arrive at the claimed invention. Wei teaches that hyaluronidase will not promote the dispersion or spreading of cells. (para. [0330]). Thus, there would be no reasonable expectation of success in combining the hyaluronidase of Wei with the cells of Frost” (Remarks, page 11).
This argument is just another slice at the teaching away argument presented above. Applicant is invited to review the above response and is reminded that the rejection is fundamentally based on a combination of Wei, Ang, and Frost, not Frost and Wei in isolation. Accordingly, this argument has been fully considered but has not been found persuasive.
(6) Applicant argues “Even assuming there was a motivation to combine the cited references as proposed in the Office Action, a skilled artisan would not have had a reasonable expectation of success to arrive at the claimed invention. Li teaches that aggregates are detrimental to the proliferation and cellular phenotype of T cells (see, e.g., Li Abstract: "T-Cell disaggregation may be important to improved cell yields and phenotype."; and Li Discussion: "Taken together, our results suggest that improved control over T-Cell aggregate size may improve proliferation capacity while tampering increased checkpoint marker expression."). Thus, there would be no reasonable expectation of success to use the aggregates taught in Li. In addition, no references taught or suggested that cells administered subcutaneously could achieve effective engraftment and expansion or could have distal therapeutic activity. Subcutaneous administration involves lymphatic absorption, subdermal tissue residence, and different cellular kinetics, raising unique risks for cell viability, activation, and persistence that are not taught or suggested by the previously-used intravenous and intratumoral/intracranial routes. Indeed, contemporaneous work in the field focused on subcutaneous administration of adjunct biologics (e.g., orthogonal IL 2 muteins) to support intravenously administered cellular therapies, rather than on subcutaneous administration of the cells themselves, underscoring the non obviousness of the claimed method. Thus, there would be no reasonable expectation of success in combining the T cell aggregates of Li with the cells of Frost” (Remarks, page 12).
The cited language from Li that Applicant provides cannot be understood as a teaching that aggregates are detrimental to the proliferation and cellular phenotype of T cells unless “disaggregation” is only understood as meaning complete disaggregation and even then it is a stretch to say that this language teaches that aggregates are detrimental because Li references controlling “aggregate size” and not complete removal of aggregates as being important for improving proliferation capacity. In addition, the fact that the art of record does not teach the differences between subcutaneous administration and other types of administration does not undermine a reasonable expectation of success in this case because the art of record teaches and provides a motivation to use subcutaneous administration. It is noted that no particular target or outcome is required by the subcutaneous administration in the instant claims and all that is required is that the cell formulation be administered subcutaneously. It is also worth noting here that, were Applicant to hang their hat on this point so to speak and amend the claims to require a particular target to be treated or an outcome of the administration, such limitations would need to be fully supported by the instant disclosure so as not to raise new issues under 35 U.S.C. 112(a). Accordingly, this argument has been fully considered but has not been found to be persuasive.
(7) Applicant argues “Unexpected results in the examples of the instant PCT-as-published (WO2021/042072A1) further demonstrate the non-obviousness of the pending claims. In Example 5 of the PCT-as-published, modified lymphocytes administered subcutaneously significantly increased the CAR cell engraftment and tumor killing in vivo versus modified lymphocytes administered intravenously. (para. [0722]-[0740] and FIGs. lA and 6-9, see, e.g., para. [0740]: "subcutaneous delivery of the modified PBMCs led to significantly better engraftment and tumor regression as compared to intravenous delivery."). In Examples 9 and 11 of the PCT-as-published, modified lymphocytes administered subcutaneously showed efficacy against systemic human Burkitt's Lymphoma in a murine model. (para. [0762]-[0768] and [0777]-[0782] and FIGs. 1C-1D and 21-22 and 25, see, e.g., para [0768]: "When delivered subcutaneously, these transduced PBMCs, which were self driving CARs expressing a lymphoproliferative element and a CAR directed to either CD19 or CD22 were capable of expanding in vivo and eliminating systemic Raji tumors.")” (Remarks, page 12).
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. Here, Applicant has not attempted any such comparison nor has Applicant provided any Affidavit to accomplish such a direct or indirect comparison. Instead, Applicant has just reiterated information already presented in the drawings of the instant Application. In addition, these “unexpected results” rely on limitations not claimed in the instant invention. Namely, CD19-expressing tumors were the targets in a B-NDG mouse xenograft model for Example 5, while NSG MHC I/II knockout mice with systemic Raji-luc tumors were used in examples 9 and 11 with CD-19 and CD-22 targeting CARs. Accordingly, this argument has been fully considered but has not been found persuasive.
Double Patenting
Claim 87 remains provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 19 of copending Application No. 18/335000 in view of WO2018/009923 (Published: 11 January, 2018) (hereinafter “Frost”) (Of Record), and WO2019/165097 (Published: 29 August, 2019) (hereinafter “Ang”) (Of Record).
Copending claim 19 recites:
“A method for performing adoptive cell therapy on a subject, comprising:a) contacting a T cell and/or an NK cell from the subject ex vivo with replication incompetent recombinant retroviral particles, wherein the replication incompetent recombinant retroviral particles comprise: i. a polynucleotide comprising one or more transcriptional units, wherein each of the one or more transcriptional units is operatively linked to a promoter active in T and/or NK cells, and wherein the one or more transcriptional units encode a first engineered polypeptide; and ii. an activation element on the surfaces of the replication incompetent recombinant retroviral particles, wherein the activation element is fused to a membrane attachment sequence, wherein said contacting facilitates transduction of the T cell and/or NK cell; b) expanding the transduced T cell and/or NK cell ex vivo for fewer than 4 cell divisions; and c) introducing the expanded T cells and/or NK cells into the subject, thereby performing adoptive cell therapy on the subject.”
Instant claim 87 recites:
“A method of administering modified T cells and/or NK cells to a subject, comprising: a. contacting T cells and/or NK cells ex vivo with replication incompetent recombinant retroviral particles comprising a polynucleotide encoding a transgene, wherein the recombinant retroviral particles modify the T cells and/or NK cells; b. collecting the modified T cells and/or NK cells to form a cell formulation comprising a suspension of the modified T cells and/or NK cells; and c. administering the cell formulation to a subject subcutaneously, wherein at least 25% of the modified T cells and/or NK cells in the cell formulation do not have the polynucleotide stably integrated into their genomes.”
Instant claim 87 is narrower than copending claim 19 in that it requires subcutaneous administration and at least 25% of the modified cells do not have the polynucleotide stably integrated into their genomes.
Frost discloses methods for genetically modifying T cells and/or NK cells (lymphocytes) with replication incompetent recombinant retroviruses, T cell and/or NK cell products of these methods, and methods of using such cells as an adoptive cell therapy (Frost, Abstract). Frost teaches modifying T cells to produce CAR T cells and their use for treating tumors (Frost, Abstract, [0005], [0429]). Frost teaches that the T cells integrate the polynucleotide into their genome (Frost, [0583]). Frost also teaches wherein at least 10, 20, or 25% of the T cells are transduced, thereby producing genetically modified T cells (Frost, [0483]). Therefore, Frost teaches wherein at least 25% of the modified lymphocytes do not have the polynucleotide stably integrated into their genomes. Ang teaches the subcutaneous administration of T cells or NK cells expressing a CAR (Ang, [0016], [0021], [00104]). Ang also teaches that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer (Ang, [00107]). Therefore, the invention claimed in instant claim 87 would have been obvious to a person having ordinary skill in the art in view of copending claim 19, Frost, and Ang.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Applicant has requested that this rejection be held in abeyance. This request is acknowledged but, since there has yet to be an indication of allowable subject matter, this rejection is maintained.
Claims 69-87 remain rejected and new claim 89 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-27 of U.S. Patent No. 11,325,948 in view of WO2018/009923 (Published: 11 January, 2018) (hereinafter “Frost”) (Of Record), US2010/0143457 (Published: 10 June, 2010) (hereinafter “Wei”), WO2019/165097 (Published: 29 August, 2019) (hereinafter “Ang”) (Of Record), WO2017/177149 (Published: 12 October, 2017) (hereinafter “Low”), and Li et al. Autoimmunity 52.3 (2019): 102-107. (published: 25 June, 2019) (hereinafter “Li”) (Of Record).
Reference Patent claim 23 recites:
“A method for genetically modifying a T cell of a subject, wherein the method comprises: contacting a population of T cells comprising the T cell ex vivo, with a population of replication incompetent recombinant retroviral particles according to claim 16, wherein said contacting is performed for less than 12 hours to facilitate membrane fusion of the T cell to the replication incompetent recombinant retroviral particle, thereby genetically modifying the T cell.”
Instant claim 69 recites:
“A cell formulation for subcutaneous administration, comprising modified lymphocytes and/or tumor infiltrating lymphocytes and wherein the cell formulation further comprises a recombinant hyaluronidase.”
Instant claim 87 recites:
“A method of administering modified T cells and/or NK cells to a subject, comprising: a. contacting T cells and/or NK cells ex vivo with replication incompetent recombinant retroviral particles comprising a polynucleotide encoding a transgene, wherein the recombinant retroviral particles modify the T cells and/or NK cells; b. collecting the modified T cells and/or NK cells to form a cell formulation comprising a suspension of the modified T cells and/or NK cells; and c. administering the cell formulation to a subject subcutaneously, wherein at least 25% of the modified T cells and/or NK cells in the cell formulation do not have the polynucleotide stably integrated into their genomes.”
Instant claim 69 is a species of product produced by the method claimed in reference patent claim 23 insofar as the genetically modified T cells produced by said method are equivalent to the instantly claimed modified lymphocytes and all that is missing from the reference claim is formulation for subcutaneous administration and a recombinant hyaluronidase. Frost discloses methods for genetically modifying T cells and/or NK cells (lymphocytes) with replication incompetent recombinant retroviruses, T cell and/or NK cell products of these methods, and methods of using such cells as an adoptive cell therapy (Frost, Abstract). Frost teaches modifying T cells to produce CAR T cells and their use for treating tumors (Frost, Abstract, [0005], [0429]). Therefore, Frost teaches modifying lymphocytes more generally with the same replication-incompetent recombinant retrovirus. Ang teaches the subcutaneous administration of T cells or NK cells expressing a CAR (Ang, [0016], [0021], [00104]). Ang also teaches that modified cells can be administered via various routes and to various sites in order to achieve a particular effect and that a particular route can provide a more immediate and effective reaction, depending on the cancer (Ang, [00107]). Wei teaches soluble PH20 polypeptides, teaches that PH20 polypeptides are human hyaluronidases, and teaches that hyaluronidases increase tissue permeability and increases the dispersion and delivery of therapeutic agents (Wei, [0006]-[0008]). Wei also teaches that PH20 is useful for treating tumors (Wei, [0017]). Therefore, instant claim 69 would have been obvious to a person having ordinary skill in the art in view of reference claim 23, Frost, Wei, and Ang. Regarding instant claims 87-88, the claimed limitations can be found throughout reference claims 23-27. Dependent claim limitations found in instant claims 70-86, and 89 can be found throughout the reference claims in view of Frost, Wei, Ang, Low, and Li.
Response to Traversal
Applicant argues against the above non-statutory double patenting rejection by reiterating arguments made previously with regard to obviousness (Remarks, page 13). These arguments have been fully considered but have not been found persuasive (see above). Therefore, this rejection is being maintained.
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.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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