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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 08/27/2021, is a 371 filing of PCT/US2020/020476, filed 02/28/2020, and claims domestic benefit to US provisional application 62/811,639, filed 02/28/2019.
Status of Application, Amendments, and/or Claims
Applicant’s response of 06/30/2026 is acknowledged. Claims 1, 19, 35, and 62-64 are amended and claims 2-5, 12-13, 16-18, 20-23, 30-31, 34, and 36-52 are cancelled. Claims 1, 6-11, 14-15, 19, 24-29, 32-33, 35, and 53-64 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 04/01/2026,
The nucleotide/amino acid sequence disclosure was objected to. Applicant’s amendment to the specification to include the incorporation by reference paragraph has overcome the objection and the objection is withdrawn.
Claim 63 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to recite “when the composition is administered to cancer cells” has overcome the rejection and the rejection is withdrawn.
Claims 62-64 were rejected under 35 USC 112(a) as being drawn to new matter. Upon further consideration and, in view of applicant’s amendment to the claims to specify that the cytotoxicity claimed is induced in the same cancer cell type used to generate the TITE as measured by MTT assay relative to untreated cells, the rejections are withdrawn.
Claims 1, 3, 6-11, 14-15, 19, 21, 24-29, 32-33, 35, and 53-61 were rejected under 35 USC 112(a) written description. Upon further consideration, the rejections are withdrawn. It is noted that the rejection of claims 62-64 are maintained and modified below as necessitated by applicant’s amendments to the claims.
Claim 3 was rejected under 35 USC 103. The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
The following grounds of objections and/or rejections are either new or modified as necessitated by applicant’s amendment to the claims.
Nucleotide and/or Amino Acid Sequence Disclosures
The Incorporation by Reference paragraph in the specification recites the file size in kilobytes (KB) rather than the required bytes. See item 1) a) iii) or 1) b) iii) below.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Interpretation
Claim 62 recites the limitation “wherein the composition induces a cytotoxicity of at least 20% in the cancer cell type used to generate the TITE, as measured by MTT assay relative to untreated cancer cells”. In the instant office action, the function recited in instant claim 62 is interpreted as limiting the composition, not the method claimed. Specifically, claim 62 is interpreted as applying to the composition recited in claim 1 when the composition is limited to one that induces 20% cytotoxicity in vitro prior to administration to the subject (i.e., is a functional property of the 10% TITE composition).
Claim Rejections - 35 USC § 112(a)
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.
Regarding claims 62-64, the instant claims depend on claims 1, 19, and 35, respectively, and recite the functional limitations that the compositions induce a cytotoxicity of “at least 20% in the cancer cell type used to generate the TITE, as measured by MTT assay relative to untreated cancer cells”.
Claim 1 is drawn to a method of treating cancer, claim 19 is drawn to a pharmaceutical composition, and claim 35 is drawn to a method of preparing a composition for treating cancer. Each of the claims recite that the composition is a cell-free composition comprising at least 10% by weight Targeting Effectors (TITE) derived from a culture comprising a bispecific antibody armed activated T cell and a cancer cell, wherein the activated T cell is derived from a T cell of a healthy donor, and the cancer cell used in the culture from which the TITE is isolated from is selected from the group consisting of a breast cancer, a pancreatic cancer, a prostate cancer, a brain cancer, a lung cancer, an ovarian cancer, a liver cancer, a leukemia, a non-Hodgkin’s lymphoma, and multiple myeloma.
It is noted that the instant specification does not provide an explicit definition for Tumor-targeting Effectors (TITE). In example 1, it is disclosed that tumor and BAT co-culture releases cytokines/chemokines/growth factors and other mediators in TITE (Specification of 06/30/2026, page 58, lines 4-7), suggesting that released components are considered TITE.
As such, each of claims 62-64 encompass a genus of methods and compositions in which TITE compositions are derived from cancer cells including a breast cancer, a pancreatic cancer, a prostate cancer, a brain cancer, a lung cancer, an ovarian cancer, a liver cancer, a leukemia, a non-Hodgkin’s lymphoma, and multiple myeloma and are limited by the functional limitation of the composition inducing a cytotoxicity of “at least 20% in the cancer cell type used to generate the TITE, as measured by MTT assay relative to untreated cancer cells”.
The instant disclosure, however, does not provide a representative number of species of the claimed genus performing the claimed function nor does the disclosure provide a structure function correlation that could be used to identify which species spanning the entire scope of the claimed genus would be capable of performing the claimed function.
The materials and methods section for the examples details the expansion and generation of activated T cells (ATC) and discloses that T cells from PBMC were activated with OKT3. Harvested ATC were armed with bispecific antibody including either anti-CD3 x anti-HER2 [HER2Bi] or anti-CD3 x anti-EGFR [EGFRBi] at pre-optimized concentrations of 50 ng/106 ATC (page 53, lines 17-24). The examples also disclose the generation of the conditioned media. The TITE was prepared by overnight culture of 1x106 tumor cells (T) and 25 x 106 of HER2 BATs or EGFR BATs (25:1 E/T ratio) overnight followed by collecting and centrifuging the cultured supernatant to remove cells and cellular debris. Control CMs were prepared using 1 x 106 tumor cells (T-CM) or 25 x 106 HER2 BATs or EGFR BATs (B-CM). The TITE were prepared and tested from at least 10-12 normal donor ATC either alone or in combination (page 53, line 25 – page 54, line 9).
Example 1 of the instant disclosure details the preparation of TITE from T cell populations of CD3+ T cells, CD4+ T cells, and CD8+ T cells armed with HER2Bi and co-cultured with MB231 tumor cells (page 57, line 30 – page 58, line 4). Breast cancer cell lines BT20 and MB231 and pancreatic cancer cell line MiaPaCa-2 were then cultured in the presence or absence of various TITE percentages (0-100%) for 5 days following imaging and MTT assay to determine the % viable cells in 3D culture. Example 1 demonstrates that TITE prepared from unfractionated activated T cells (CD3+ T cells showed marked killing of BT20 tumor spheres compared to TITE generated from CD4+ or CD8+ T cell fractions (pages 57-58, Example 1).
Example 6 discloses that the activity of TITE is retained in >10 kDa and <50 kDa molecular weight fractions and that fractions below 3kDa, <10kDa, or heat treated showed low or no cytotoxic activity. Since functional activity was heat-sensitive, the factor(s) appeared to be protein(s). Soluble factor(s) between 10 to 50 kDa molecular weight retained immune activating activity (page 59, lines 21-27).
Example 8 studied the cytotoxicity of TITE against multiple cancer cell lines. In the example, TITE were examined for their effects on various tumor cell lines. Effects of various concentrations (5%, 10%, and 25%) B-CM or TITE on tumor cells including breast cancer cell lines: SKBR3, and MB231; pancreatic cancer cell lines: MiaPaCa-2, L3.6p1, and CoLo-356; the epidermoid carcinoma cell line: A431; and the lung cancer cell line H292. Results are reported in Fig. 1I. The example additionally studied 25% TITE at 72 hours in the treatment of cell lines including those above and also breast cancer cell line MCF-7; colorectal cancer cell line HCT-8; lung cancer cell line A549; and head and neck cancer cell line HN6.
It is noted that it is not clear from the example how the doses of 5%, 10%, and 25% were calculated or what exactly these percentages reflect. If these are percentages of the TITE by weight in the compositions added to the cultures, it is unclear how much of the composition was added and what the final amount of the TITE was in the cultures. The example also does not explicitly disclose what the components of the TITE composition was or the amount of the contained components.
The example demonstrates that, at 5%, TITE mediated tumor lysis was very low to none, the cytotoxicity at 10% TITE ranged from 10-50% against various cell lines. The TITE mediated cytotoxicity was consistently high across multiple cell lines at 72 hours by MTT assay. A 25% dose of TITE showed highly significant cytotoxicity against MB231, MCF-7, SKBR3, MiaPaCa-2, L3.6p1, CoLo-356, HCT8, H292, A549, HN6 compared to B-CM (control supernatant from BITE only) at 72 hours. One of the head and neck cell lines H46 showed high cytotoxicity by both B-CM and TITE, while HN12 showed no killing by either B-CM or TITE. The results of the study are shown in Fig. 1I (page 60, lines 9-22), which is duplicated below for convenience.
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The cancer types represented by the cell lines used include the following:
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As such, the results presented are for breast cancer, pancreatic cancer, epidermoid carcinoma, lung cancer, colorectal cancer, and head and neck cancer cell lines.
The results do demonstrate that, under the tested conditions and with the tested compositions, treatment of some cancer cell lines with TITE result in cytotoxicity, including cytotoxicity that is at least 20%. However, the results do not demonstrate such responses for all of the types of cancers recited in the instant claims. For instance, the example does not demonstrate at least 20% cytotoxicity in prostate cancer, brain cancer, ovarian cancer, liver cancer, leukemia, non-Hodgkin’s lymphoma, or multiple myeloma, all of which are encompassed by the instant claims. Additionally, claims 62-64 require the comparison to be “relative to untreated cancer cells” however, there is no clear indication that the results presented in the disclosure are relative to untreated cancer cells and there does not appear to be a control that was not treated. Rather, the comparison is made to B-CM treated controls, which appears to be compositions generated using BATs alone with no cancer cells.
Additionally, the results also suggest that not all cancer cell lines had the same response and resulting cytotoxicity. For instance, as discussed in the example, and shown in Fig. 1I, the head and neck cell line HN6 had cytotoxicity that was greater than 20%; however, the head and neck cell line HN12 showed no killing by controls or TITE compositions. Furthermore, if the % values reported represent the % by weight TITE, Fig. 1I demonstrates that, with 10% TITE, at whatever amount was administered, pancreatic tumor models L3.6 and CoLo 356 both had less than 20% cytotoxicity, further demonstrating that the cancer type and even cell line may play a role in the amount of cytotoxicity that can be achieved.
While it is unclear what was comprised in the TITE composition used in Example 8, Example 12 studied the soluble factors including cytokines, chemokines, and growth factors in supernatants from tumor alone T-CM, BATs alone (BCM) or tumor cells + BATs co-culture (TITE) using the Luminex multiplex technology. The example discloses that TITE differed in their cytokine/growth factor profile depending on the tumor cell line. However, tumor cell line MB231 co-cultured with BATs secreted high levels of Th1 cytokines IFN-γ, TNF-α, Granzyme B, GM-CSF, G-CSF, proliferation cytokines including Flt3L, IL-2, IL-3, moderate levels of Th2 cytokines IL-10, IL-5, IL-6, and IL-13, and growth factors CD40L, VEGF, and PDGF-AA. The levels of chemokines IP-10, MIP-1a, MIP-1b, RANTES, GRO-a, GRO-b, and IL-8 also increased significantly in TITE compared to T-CM and B-CM levels of cytokine and chemokines. The values of cytokines, chemokines, and growth factors are shown in Fig. 2 (page 61, line 24- page 62, line 5).
Example 15 also teaches the presence of miRNA in TITE compositions (page 62, line 28 – page 63, line 14).
Examples 12 and 15 suggest that the content of the TITE compositions can vary significantly and is also dependent on the cancer cell that the BAT is cultured with.
Example 16 provides results from mouse models using the MB-231 tumor cell line. The example studied IV vs intratumoral (IT) administration of TITE and disclose that tumor growth was significantly delayed after 2 weeks when TITE was injected by IV; however, no tumor regression or cures were noted (page 63, line 15 - page 64, line 1; Fig. 4).
As discussed above, the disclosure does not provide a representative number of species of the claimed genus performing the claimed function. The disclosure also does not provide a structure-function correlation that would allow for the predictable identification of which species within the claimed genus would be capable of performing the claimed functions of treating any cancer and additionally having a cytotoxicity of at least 20%, as measured by MTT assay relative to untreated cancer cells..
The prior art also does not provide a representative number of species of the claimed genus or a structure-function relationship that would allow such determination.
For instance, Ross, S.L., et al (2017) Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing PLoS ONE 12(8); e0183390, pages 1-24 studied the mechanism of bystander killing of EGFR-negative cells using crude supernatant from activated T cells. Ross discloses that crude supernatants containing medium and T cells, but not cell-free medium removed from such cultures, induced significant cytotoxicity when transferred to EGFR-negative cells (page 11, last paragraph). Ross teaches that IFNγ and TNFα are produced at high levels by BITE activated T cells, but clarified supernatants containing T cell produced cytokines were not directly cytotoxic to SW620 cells, which is a colorectal cancer cell line. Likewise, exogenously added recombinant IFNγ and TNFα, alone or in combination, were not cytotoxic to the cell lines used in the study, even at concentrations exceeding those produced by BiTE activated T cells. However, T cells activated by EGFR BiTE in the presence of EGFR-positive cells (i.e., BiTE1-activated T cells) lysed EGFR-negative cells. The degree of lysis was significantly higher when the EGFR-negative cells were pretreated with IFNγ and TNFα (Fig 5C). These data indicate that these cytokines, while not directly cytotoxic, acted on EGFR-negative cells to increase their sensitivity to lysis by BiTE-activated T cells (page 14, paragraph 1).
The teachings of Ross demonstrate that supernatant from activated T cells, which also comprises cytokines including IFNγ and TNFα, were not cytotoxic to SW620 cells and, even when tested alone at high concentrations, IFNγ and TNFα alone did not cause cytotoxicity to the cells. Ross demonstrates further unpredictability in the claimed methods/compositions and the treatment of cancer further suggesting that the composition of the TITE matters as well as the cancer cell lines that are treated. Ross does not demonstrate any species of the instantly claimed methods/composition performing the claimed function nor does Ross provide a structure function correlation that could be used to support the full scope of the claimed genus.
US 2004/0241183 A1 (Hasumi, K., et al) 02 Dec 2004 teaches an adjuvant derived from human lymphocytes that can be used in combination with traditional vaccines or cancer immunotherapy to enhance the response of the patient’s immune system to the vaccine or other immunotherapeutic agent (page 1, [0002]).
US’183 teaches that several investigators have described the use of various cell-free culture supernatants, also referred to as “conditioned media, as DC maturation agents. These media contain more or less well defined mixtures of cytokines. Monocyte conditioned media containing IFNα, IL-1β, IL-6, and TNFα, has been shown to induce expression of CD83 and p55, surface molecules that are characteristic of mature DC. However, when combinations of these cytokines were added to immature DC at concentrations comparable to those found in the conditioned media, they were less effective in maturing DC compared to MCM, suggesting that additional components were required to affect full maturation of DC (pages 1-2, [0011]). In one study, prepared conditioned media (TCCM) was prepared by culturing isolated T cells with anti-CD3 monoclonal antibodies that had been adhered to plastic surfaces. This media was able to mature immature DC that had been generated from monocytes in culture. Interestingly, different clones of anti-CD3 induced different quantities of soluble CD40 ligand and IFNγ, and these differences were reflected in the capacity of the media to mature DC (page 2, [0012]). US’183 studied the use of conditioned media in combination with vaccine antigens under the hypothesis that the combination would result in more antigen presenting cells presenting the vaccine antigen to T lymphocytes and B cells (page 2, [0014]). US’183 teaches lymphocyte conditioned medium obtained from PBMC stimulated with anti-CD3/CD28 coated beads, which comprised cytokines, and chemokines (page 2, [0018]-[0019]). Additionally, US’183 demonstrates the ability of the LCM to stimulate PBMCs both alone and in combination with tetanus toxoid antigen, but teaches that the response to the specific antigen was significantly augmented when LCM was used alone (Figs 5A and B).
While US’183 teaches the use of cell-free conditioned medium as a means to enhance immune stimulation responses in the treatment of cancer, US’183 also demonstrates the impact of the components and amount of components in the supernatants on the results obtained. For instance, US’183 teaches studies where different clones of anti-CD3 antibodies generated different quantities of effectors and; therefore, provided different outcomes. US’183 does suggest that LCM can act to stimulate PBMCs; however, US’183 does not provide a representative number of species or a structure function correlation that supports the entire scope of the instantly claimed invention.
As discussed in detail above, neither the disclosure, nor the prior art, provide a representative number of species of the claimed genus performing the claimed functions nor does the disclosure or prior art provide a structure-function correlation that would allow for the predictable identification of which species within the claimed genus would perform the claimed function. As such, the claims were not found to meet the written description requirement of 35 USC 112(a).
Response to Arguments
Applicant’s arguments regarding the rejections under 35 USC 112(a) Written description in the response filed 06/30/2026 have been fully considered, but were not persuasive.
Applicant argues that the claims have been amended to directly correspond to experimental outcomes found in the specification. Applicant further argues that, due to the nature of the presently disclosed subject matter, the potential for heterogeneity and the lack of a direct structure-function relationship does not require the identification of the exact species that performed the claimed function of TITE. Applicant argues that, as there is heterogeneity of the exact components of TITE based on the cancer cell type used at the time of TITE generation, the expectation of a distinct structure-function relationship is improper and does not fit the context of the presently claimed subject matter.
These arguments are not persuasive.
The claims have been amended to recite that the TITE are isolated using cancer cells selected from breast cancer, pancreatic cancer, prostate cancer, brain cancer, lung cancer, ovarian cancer, liver, leukemia, non-Hodgkin’s lymphoma, and multiple myeloma; however, it is not clear that the experimental outcomes in the specification support the functional limitations recited in claims 62-64 in all of the claimed cancer cell lines. For instance, as discussed in detail in the modified rejections of the instant office action, it appears that the examples only demonstrate the recited functions for cell lines representative of breast cancer, pancreatic cancer, and lung cancer. The claim; however, also encompasses prostate cancer, brain cancer, ovarian cancer, liver cancer, leukemia, non-Hodgkin’s lymphoma, and multiple myeloma. The experimental outcomes presented in the specification and the prior art also suggest that the cancer type and cell line impact the % cytotoxicity that is observed.
The examples of the disclosure, and the prior art, also suggests that the contents of the TITE matters with regards to the cytotoxicity that is achieved. For instance, as discussed in the rejection and in the specification, Example 6 discloses that the activity of the TITE is retained in the >10 kDa and <50 kDa molecular weight fractions and that fractions below 3 kDa, <10 kDa, or heat treated showed low or no cytotoxicity. The example also suggests that the factors appear to be proteins, since they are heat sensitive. The teachings of Ross and US’183, which are discussed in detail in the rejection, also suggest that the content of the TITE changes cytotoxicity. The teachings of US’183 also suggests that the methods of making the TITE impacts the characteristics of the TITE composition. For instance, as discussed in the rejection, US’183 teaches that different clones of anti-CD3 antibody, used to stimulate the T cells, generated different quantities of effectors and provided different outcomes.
Applicant’s arguments also appear to support the conclusion that the art is not predictable in terms of the amount of cytotoxicity that can be achieved as applicant discusses heterogeneity and a lack of structure-function relationship. While applicant argues that the expectation of a distinct structure-function relationship is improper and does not fit the context of the presently claimed subject matter, when the claims are drawn to a genus, such a relationship can be supplied in place of a representative number of species reduced to practice in order to demonstrate predictability and possession of the claimed invention.
For instance, MPEP 2163 II.A.3.a.ii. states “[t]he written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…, reduction to drawings…, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.”
In this case, as discussed in the rejection, claims 62-64 encompass a genus of methods/compositions which comprise TITE compositions, containing any TITE components, obtained using one of the recited cancers and any BAT and recite the functional limitation that the composition induces a cytotoxicity of at least 20% in the cancer cell type used to generate the TITE, as measured by MTT assay relative to untreated cancer cells. As discussed in detail in the rejection, applicant does not provide a representative number of species of the claimed genus performing the claimed function. This combined with the expected heterogeneity and the lack of a known or disclosed correlation between function and structure is insufficient to show that applicant was in possession of the claimed genus at the time of the effective filing date.
Applicant further argues that the lack of HN12 response in vitro falls outside of the scope of the claimed invention and that; therefore, any alleged deficiency associated with that example is not relevant to the claimed subject matter or the requirements of 112(a). Applicant argues that variability in treatment response among different cancer subtypes is expected, and reliance on such variability to suggest a deficiency in written description is misplaced.
These arguments are not persuasive.
While the claims have been amended and do not encompass head and neck cancer, which HN12 is a cell line of, the examples pertaining to HN12 still demonstrate a lack of predictability in the art and the content is therefore relevant to the rejections of the instant office action. Additionally, while variability in treatment among cell subtypes, and even cell lines, can be expected, claims 62-64 limit the compositions by reciting a specific function that the compositions are required to have. Because the art is not predictable, as demonstrated by the examples in the instant specification, and also the prior art, one of ordinary skill in the art would not be able to predictably identify which TITE compositions would have the claimed functional characteristics. As such, one of ordinary skill in the art would not reasonably identify that applicant was in possession of the full scope of the claimed genus that is encompassed by claims 62-64.
Applicant further argues that the rejection asserts that the specification does not provide a sufficient structure-function correlation and the amount of TITE used in the experimental results is not well defined. Regarding the 5%, 10%, and 25% TITE in Example 8 and Fig. 1l, applicant argues that the pending claims define the recited percentages as referring to the weight of the TITE in the claimed compositions. Applicant argues that the rejection relies on the absence of repeated explanatory language within the labels of Fig. 1l, but that the claim specifically cites “by weight” and the specification consistently describes TITE compositions in terms of percentage based formulations.
This argument is not persuasive.
It is acknowledged that the 5%, 10%, and 25% TITE in Example 8 and Fig. 1l, and that claimed, is disclosed as pertaining to the percentage of TITE in the composition by weight. The rejection does not question what the percentage represents, but rather, how it was calculated (i.e. what components are included and how much) and what amount or dosage was used in the studies. For instance, a composition could comprise 5% by weight TITE, but any amount of the composition could be added to the studies which would impact the amount of TITE that is added. The concentration of the composition itself may be defined, but neither the claims nor the specification elaborate on how much of the composition was required in order to achieve the experimental results that are claimed.
Applicant further argues that the claimed composition is a secreted therapeutic composition derived from biological culture systems and a person of ordinary skill in the art would understand that the precise composition of secreted therapeutic factors can inherently vary depending on the biological source system and cancer context from which TITE is generated. Applicant argues that the TITE can include cytokines, chemokines, growth factors, and miRNA. Applicant further argues that an ordinarily skilled artisan would reasonably understand the specification to demonstrate possession of the presently claimed invention without requiring exhaustive identification of each individual secreted component within each preparation of TITE.
As stated by applicant in the response, and as discussed in detail above, the composition of the TITE can inherently vary depending on a variety of factors such as the biological source system and cancer context from which the TITE is generated. While the TITE can include cytokines, chemokines, growth factors, and miRNA, that does not indicate that all TITE would include such factors or that they would be included in amounts that are sufficient to induce at least 20% cytotoxicity as is recited in instant claims 62-64. Additionally, exhaustive identification of each individual secreted component within each preparation of TITE would not be necessary if the composition structure-function correlation was predictable or if applicant provided a representative number of species of the claimed invention performing the claimed function.
MPEP 2163 II.A.3.a.ii. states "[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).
Applicant; however, does not provide a representative number of species or a structure-function correlation that could be used to predictably identify which TITE compositions would be capable of performing the functions recited in instant claims 62-64. For these reasons, the rejections under 35 USC 112(a) Written Description are maintained for these claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-11, 19, 21, 24-29, 35, 53-57, and 58-61 are rejected under 35 U.S.C. 103 as being unpatentable over US 2004/0241183 A1 (Hasumi, K., et al) 02 Dec 2004 in view of Wong, R., et al (2013) Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells haematologica 98(12); 1930-1938, US 8,012,470 B2 (Lindhofer, H., et al) 06 Sept 2011, US 2003/0185823 A1 (L.G. Lum and G. Elfenbein) 02 Oct 2003, and US 2016/0263193 A1 (Vidal Fayos, F.) 15 Sept 2016.
US’183 teaches an adjuvant derived from human lymphocytes that can be used in combination with traditional vaccines or cancer immunotherapy to enhance the response of the patient’s immune system to vaccines or other immunotherapeutic agents. US’183 teaches that the adjuvant is derived from the supernatant collected from cultured activated lymphocytes (abstract).
US’183 further teaches that several investigators have described the use of various cell-free culture supernatants, also referred to as “conditioned media” as DC maturation agents. These media contain more or less well defined mixtures of cytokines (pages 1-2, [0011]).
US’183 teaches a method of enhancing immune response in a mammal comprising administering lymphocyte conditioned medium (LCM), which is the supernatant derived from activated human lymphocyte cells cultured with growth media, in combination with the vaccine antigen. Preferably, the mammal is human. Culture methods and protocols are standard and known in the art. Human, or other mammal depending on the mammal to be treated, peripheral blood mononuclear cells (PBMC) obtained from any source are diluted in commercially available tissue culture growth media. The cells are incubated with an activation agent consisting of beads coated with antibodies to CD3/CD28. On about day 3, cells and beads are separated from the culture media and the cells and beads are resuspended in additional growth media as needed. To harvest the cells, they are resuspended in centrifuge tubes and pelleted after which the supernatant can be drawn off with a pipette and stored for use (page 3, [0032]). US’183 discloses an exemplary embodiment in which the human PBMC used for preparation of the conditioned media were separated from leukapheresis products of normal healthy donors (page 4, [0038]).
US’183 teaches that the disclosed supernatant is suitable for use with a large variety of vaccines including cancer peptide vaccines using antigens, peptide, DNA fragments, and/or any other molecule species on the surface or within the cancer cell (pages 3-4, [0035]).
US’183 performed studies analyzing the cytokines and chemokines in the LCM (page 4, [0046]). US’183 reports that a whole battery of soluble mediators were identified, including GM-CSF and IL-4; inflammatory cytokines including IL-1β, IL-6, PGE2, TNFα, and IFNγ; chemokines including MCP-1, MIP1, and RANTES, and sCD40L (page 5, [0059] and Table 2).
US’183 teaches that the cytokines and chemokines identified in the LCM preparations are known to participate in the generation of immune responses by their autocrine or paracrine effect on APC and responding T and B cells (page 2, [0018]).
US’183 further studied the ability of LCM to enhance PBMC response to tetanus toxoid and teaches that, in the absence of LCM and other cytokines, PBMC showed low levels of response to TT; however, with the addition of LCM, the response to TT significant increased at day 6. It is important to point out that the LCM alone induced DNA synthesis in PBMC even in the absence of specific antigen; nevertheless, the response to the specific antigen was significantly augmented (page 3, [0031]; page 6, [0065]; Fig. 5A). In Fig. 5A, US’183 demonstrates significant increases in PBMC stimulation in the presence of LCM only or LCM + TT compared to controls.
US’183, however, does not disclose that the activation agent cultured with the PBMCs to obtain the LCM is bispecific antibody armed activated T cells (BATs) and a cancer cell selected from those recited in the instant claims. US’183 also does not disclose that the composition comprises 10% by weight TITE.
Wong teaches that the CD19/CD3 bispecific antibody construct blinatumomab (AMG103 or MT103) has been tested clinically in non-Hodgkin’s lymphoma and acute lymphoblastic leukemia but has not been assessed in chronic lymphocytic leukemia. Wong investigated whether blinatumomab could overcome T cell dysfunction in chronic lymphocytic leukemia in vitro. Blinatumomab was tested on peripheral blood mononuclear cells from 28 patients. T-cell activation and function, as well as cytotoxicity against leukemic tumor cells were measured. Blinatumomab induced T-cell activation, proliferation, cytokine secretion and granzyme B release in a manner similar to that occurring with stimulation with anti-CD3/anti-CD28 beads (abstract). Wong teaches that blinatumomab is a bi-specific, single chain antibody construct classified as a bi-specific T cell engager. It is formed by the fusion of an anti-CD3 scFv with an anti-CD19 scFv via a short peptide linker. These bi-specific antibodies can recruit immune effector cells to the tumor cell surface and promote immune synapse formation (page 1930, right column, paragraph 2).
Wong teaches cell cultures in which PBMC were incubated in media for 3-7 days. Blinatumomab was added to the PBMC cultures at a concentration of 10 or 100 ng/mL. Human T-cell activator CD3/CD28 dynabeads were used as a positive control for T cell activation. For absolute counts of T cells and CLL cells, an anti-CD3 antibody was used as a positive control (page 1931, Cell cultures).
Wong teaches that the expansion of CD4+ and CD8+ T cell numbers in blintumomab-treated cultures suggested that the bi-specific antibody could induce T-cell proliferation. Similar results were obtained using anti-CD3/anti-CD28 beads. Furthermore, PBMC cultured with blinatumomab showed significant up-regulation of the activation markers CD38, HLA-DR, and CD69. Increased expression of HLA-DR on CLL cells was also increased suggesting an activation effect which required both CLL cells and T cells in the culture (paragraph bridging pages 1932 and 1933).
Wong further studied whether the difference in cytotoxic effect between blinatumomab and anti-CD3/anti-CD28 activated T cells was cytokine-mediated. PBMC cultures treated with anti-CD3/anti-CD28 beads were analyzed for the presence of 11 different cytokines. Three cytokines, including IFN-γ, TNF-α, and TNF-β, and one chemokine, IL-8, were found to be significantly increased in the supernatant of cultures with blinatumomab or CD3/CD28 beads (page 1934, left column, paragraph 1). Wong teaches that there was no obvious difference in the capacity of blinatumomab to induce T-cell activation based on several criteria, such as proliferation, cytokine release or cytotoxic granule release, when compared to anti-CD3/anti-CD28 beads (page 1934, right column, paragraph 2).
US’470 teaches a composition comprising activated peripheral blood mononucleated cells and non-viable tumor cells from the same individual, the composition obtained by incubating ex vivo: a) tumor cells isolated from a patient and treated to prevent survival following reinfusion; b) peripheral blood mononucleated cells from the patient; and c) an intact heterologous bispecific antibody (column 12, claim 1). US’470 further teaches that the cells can be T cells obtained from aphaeresis (column 11, lines 8-9 and 15-19). US’470 teaches long-term incubation and culturing of the composition (column 11, lines 2-15).
US’470 further teaches a method for inducing an anti-tumor immunity in a patient comprising administering the composition to the patient (column 14, claim 5) and that such compositions are used in the treatment of tumor diseases by inducing the anti-tumor immunity (column 2, lines 5-8). US’470 teaches that tumor immunity is defined as activating the immune system of the body in an organism against the autologous tumor in such a way that a long-term or even permanent destruction and/or control of the autologous tumor is achieved (column 2, lines 30-34).
US’470 teaches a tumor cell is a cell which has lost its normal function by one or more mutations or wherein its normal function has been changed and, due to these mutations, the tumor cells are able to propagate in an uncontrolled manner (column 2, lines 25-29). US’470 teaches that every kind of tumor falling under this definition can be treated with the present method, particularly epithelial tumors, colon carcinomas, mammary (breast) carcinomas, ovarian carcinomas, carcinomas of the lungs, liver tumors, leukemias, and lymphomas (column 2, lines 35-42).
US’470 further teaches that by the bispecific antibodies useful according to the invention, T cells are activated and redirected against the tumor cells. The bispecific antibodies are disclosed as being heterologous intact bispecific antibodies which can be monoclonal, chimeric, recombinant synthetic, semi-synthetic, or chemically modified (column 6, lines 58-60; column 8, lines 7-11). US’470 further teaches that the bispecific antibodies are able to bind to the T cell receptor complex of the T cell by one binding arm and to tumor-associated antigens on the tumor cells by the second binding arm. Thereby, they activate T cells which destroy the tumor cells by releasing cytokines or apoptosis mediating mechanisms (column 4, lines 53-58). US’470 discloses studies in which cytokines including IL-2 and IL-6 were observed in cultures comprising the composition (Figure 3). US’470 further teaches that T cell redirecting bispecific antibodies are known to release TNF-α resulting from activation of the T cell and spatial proximity of the tumor cell leading to destruction of the tumor cell (column 1, lines 49-55).
As US’470 teaches cytokines that aid in destroying the tumor, US’470 is teaching compositions that comprise tumor-targeting effectors according to the instant disclosure. Additionally, the cytokines disclosed by US’470 meet the instant claim limitations of the TITE comprising Th1 cytokines, specifically TNF-α, proliferation inducing cytokines, specifically IL-2, and Th2 cytokines, specifically IL-6.
US’823 teaches in vivo activated T cells armed with chemically heteroconjugated bispecific monoclonal antibodies generated against tumor antigens. US’823 teaches that the T cells are from patients diagnosed with malignancies such as breast cancer, prostate cancer, renal tumors, or other malignancies or are allogeneic (page 1, [0003]; page 39, claim 5). US’823 further teaches that the lymphocytes are obtained by leukapheresis (page 19, [0248]) and the T cell subset may be CD8+, unfractionated CD3+, or CD4+ T cells (page 25, [0338]).
US’823 teaches that peripheral blood mononuclear cells are isolated and the T cells are activated by ex vivo stimulation with either soluble anti-CD3 monoclonal antibody, or anti-CD3 and anti-CD28 monoclonal antibodies attached to a solid support. The activated T cells are expanded in the presence of about 100 IU/ml of IL-2. Once a suitable number of activated T cells is achieved, the T cells are armed with bispecific antibodies. The bispecific antibodies are capable of binding to the T cell receptor complex of a T cell and to a tumor-associated antigen on a tumor cell (page 2, [0015]). US’823 further teaches that the anti-CD3 and anti-CD28 antibodies can be immobilized on a bead, such as, for example, Dynal beads (page 7, [0103]). US’823 further teaches a bead ratio of 3:1 beads/cells (page 20, [0256]).
US’823 teaches that immune cell activity that can be measured includes enhanced cytokine production, including specific measurements for cytokines such as IFN-γ, GM-CSF, or TNF-α (page 6, [0088]).
US’823 further teaches pharmaceutical compositions comprising the T cells bound to antibodies and pharmaceutically acceptable excipients (page 42, claim 97). US’823 teaches that the compositions are used for the treatment of tumors and that treatment is defined as generally meaning obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof (page 4, [0069]; page 6, [0090]).
US’193 teaches a method for preparing serums comprising cytokines and coagulation factors comprising submitting a biological sample comprising platelets and/or leukocytes to different steps of different gravity force to obtain supernatants with high concentrations of cytokines and coagulation factors (abstract). US’193 further teaches that the cytokines in the supernatant produced include TNF-α and interleukins including IL-6 and IL-1β (page 16, tables 1 and 2).
US’193 teaches compositions with 10%-30% w/w cytokine rich serum (page 3, [0043]). US’193 also studied the effect of 10%, 20%, 50%, and 80% w/w cytokine rich serum on bone marrow cell growth and demonstrates that such concentrations are capable of cellular effects (page 3, [0043]; figure 6).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the methods and compositions disclosed by US’183 by using a bispecific antibody cultured with T cells and cancer cells to produce the lymphocyte conditioned media based on the teachings of Wong and further supported by US’470. It would have further been obvious to substitute the bispecific antibody in the method with the bispecific antibody armed activated T cells disclosed by US’823. It would have further been obvious to use cancer cells including non-Hodgkin’s lymphoma, ALL, CLL, breast cancer, ovarian cancer, lung cancer, liver, leukemias, lymphomas, prostate cancer, or renal cancer, based on the disclosures of Wong, US’470, and US’823. It would have also been obvious to use the methods disclosed by US’193 to obtain supernatants with high concentrations of cytokines and coagulation factors resulting in at least 10% w/w cytokine rich serum compositions.
It would have been obvious to produce the LCM of US’183 using a bispecific antibody cultured with T cells and cancer cells as Wong demonstrates that culturing a bispecific antibody in combination with cancer cells and T cells (from PBMC) induces t-cell activation, proliferation, cytokine secretion, and granzyme B release in a manner similar to that occurring with stimulation with anti-CD3/anti-CD28 beads. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. Additionally, Wong teaches increases in IFN-γ, TNF-α, TNF-β, and IL-8 in cultures which overlaps with the cytokines/chemokines taught by US’183. The use of bispecific antibodies, T cells, and cancer cells is further supported by US’470, which demonstrates methods of culturing bispecific antibodies, T cells, and cancer cells and demonstrates that such methods result in increases in factors including TNF-α, IL-2, and IL-6.
An ordinarily skilled artisan would have been motivated substitute the armed activated T cells of US’823 for the bispecific antibody and T cells as US’823 teaches that arming activated T cells with the bispecific antibody makes every T cell an antigen-specific CTL and allows the activated T cell to target the cancer cells multiple times, secrete tumoricidal cytokines, secrete chemokines, and survive longer without being rearmed with a bispecific antibody (abstract). An ordinarily skilled artisan would have had a reasonable expectation of success as the bispecific antibody armed activated T cells would still function in the compositions/methods taught by Wong by binding both the T cell and the cultured tumor cell.
It would have been obvious to use cancer cells selected from non-Hodgkin’s lymphoma, ALL, CLL, breast cancer, ovarian cancer, lung cancer, liver, leukemias, lymphomas, prostate cancer, or renal cancer, as Wong and US’470 demonstrate the culturing of bispecific antibodies cultured with T cells and the cancer cells to generate LCM and US’823 teaches the culturing of armed activated T cells for use with the cancers and also demonstrates that the combination secretes tumoricidal cytokines and chemokines. An ordinarily skilled artisan would have had a reasonable expectation of success as US’183 teaches the application of the methods and compositions disclosed in the treatment of cancer and Wong, US’470, and US’823 all teach the treatment of cancer using methods in which T cells are activated resulting in the secretion of cytokines and chemokines.
It would have been obvious to use the methods of US’193 to obtain supernatants with high concentrations of cytokines and coagulation factors including at least 10%-30% w/w of the effectors in the composition as US’193 demonstrates that the concentration of cytokines and coagulation factors to obtain higher w/w %s had been practiced in the prior art. Additionally, US’193 demonstrates that these concentrations of effectors can have cellular effects. An ordinarily skilled artisan would have had a reasonable expectation of success as US’193 teaches methods of concentrating cytokines and coagulation factors, such as the use of gravitational forces, and teaches cytokines and growth factors that overlap with those taught by the combination of applied references including TNF-α, IL-6, and IL-1β.
Additionally, the determination of the optimal concentration of effectors in the composition and the determination of the effective dose of effectors administered to the patient is considered to be routine optimization where considerations were known in the art. MPEP 2144.05 (II) A. states "’[W]here 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)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, the combination of applied references suggest the use of lymphocyte conditioned media as a means to treat cancer, particularly in combination with antigens and/or immunotherapy. The combination of applied references suggest that the LCM is effective due to the cytokines, chemokines, and growth factors that are produced during culture and the art also demonstrates the ability to concentrate these effectors to obtain higher concentration cultures, including 10% w/w and higher. It would have been obvious to use these teachings as a starting point for routine optimization to determine optimal composition concentrations and administration amounts to treat a disease, such as cancer, particularly in combination with an antigen vaccine or immunotherapy agent.
It is noted that, while the combination of applied references suggest the combination of LCM and vaccines or immunotherapy agents in the treatment of cancer, the inclusion of additional, unrecited elements, such as vaccine antigens and immunotherapy agents, would still meet the instant claim limitations as the claims use “comprising” language with regards to the claimed methods and compositions. The instant specification defines “comprising” as being synonymous with “including,” “containing,” or “characterized by,” and being inclusive or open-ended and not excluding additional, unrecited elements and/or method steps. “comprising” is a term of art used in claim language which means that the named elements are present, but other elements can be added and still form a composition or method within the scope of the presently disclosed subject matter (page 11, lines 7-16). Therefore, the methods and compositions claimed encompass methods and compositions comprising additional, unrecited, elements including additional active agents such as vaccines and immunotherapy agents.
Regarding claims 53, 57, and 61, the range of 10%-30% taught by US’193 overlaps with the instantly claimed range of about 10% by weight to about 25% by weight. It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have pursued concentrations throughout the range disclosed by US’193, including those claimed, as the range taught by US’193 is shown to have cellular effects. MPEP 2144.05 I. states “in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”
Claims 14-15 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over US 2004/0241183 A1 (Hasumi, K., et al) 02 Dec 2004 in view of Wong, R., et al (2013) Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells haematologica 98(12); 1930-1938, US 8,012,470 B2 (Lindhofer, H., et al) 06 Sept 2011, US 2003/0185823 A1 (L.G. Lum and G. Elfenbein) 02 Oct 2003, and US 2016/0263193 A1 (Vidal Fayos, F.) 15 Sept 2016 as applied to claims 1 and 19 above, and in further view of Rodriguez-Galan, et al (2018) Control of Immunoregulatory Molecules by miRNAs in T cell activation Frontiers in Immunology 9(2148); 1-10.
The combination of US’183, Wong, US’470, US’823, and US’193 teach the method of claim 1 and the composition of claim 19 as discussed above.
The combination of US’183, Wong, US’470, US’823, and US’193, however, does not disclose that the composition comprising the TITE comprises a miRNA or that the miRNA is selected from those recited in instant claims 15 and 33.
Rodriguez-Galan teaches that miRNA targeting of key immunoregulatory molecules fine-tunes the immune response and that miRNA expression changes during T cell activation. Rodriguez-Galan provides a review regarding miRNAs that are differentially expressed during T cell stimulation (abstract).
Rodriguez-Galan teaches that during T cell activation and stimulation, miRNAs including miR-155, miR-17-5p, miR-20a-5p, and miR-106-5p are upregulated (page 1, paragraph 3; page 3, Figure 1).
Based on the teachings of Rodriguez-Galan, an ordinarily skilled artisan would have reasonably expected that the TITE composition disclosed by the combination of US’183, Wong, US’470, US’823, and US’193 would comprise miRNAs including miR-155, miR-17-5p, miR-20a-5p, and miR-106-5p An ordinarily skilled artisan would have expected the composition to comprise these miRNAs as Rodriguez-Galan teaches miRNAs that are differentially expressed during T cell stimulation and the combination of US’470, US’823, US’183, and US’193 is teaching a method and composition comprising activated/stimulated T cells.
Response to Arguments
Applicant’s arguments in the response filed 06/30/2026 have been fully considered, but are not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that the rejection relies on impermissible hindsight and does not provide a reasoned basis for combining the cited references to arrive at the instantly claimed invention. Applicant goes on to discuss the teachings of each reference and how they differ to the instantly claimed invention.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Additionally, 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). See MPEP 2145 (IV).
In the rejection, each modification made to the primary reference, US’183, is discussed in detail including a rationale of why and how it would be obvious to combine the references and why there would be a reasonable expectation of success. Applicant does not provide any specific argument concerning any specific modification that is proposed in the rejection.
With regards to US’183 (referenced in the response as “Hasumi”), applicant argues that reliance on the conditioned media in US’183 is misplaced and that it is a general term that encompasses a wide range of known materials and does not support obviousness. Additionally, applicant argues that US’183 teaches that the media is distinctly meant for combination alongside a vaccine antigen, whereas the disclosure at hand is not meant to bolster the effects of separately combined factor into the conditioned media.
This argument is not persuasive.
Even if conditioned media was a general term that encompassed a wide range of known materials, the independent claims of the instant invention do not require any specific materials in the composition other than for the composition to meet the limitation of comprising “TITE”. Additionally, the instant disclosure does not specifically disclose a limiting definition for TITE and; therefore, TITE can include any tumor targeting effectors and still meet the instant claim limitations. It is noted that example 1 of the disclosure does state that the tumor and BAT co-cultures released cytokines/chemokines/growth factors and other mediators in TITE, indicating that compositions of cytokines/chemokines/growth factors meet the limitations of compositions comprising TITE.
As discussed in detail in the rejection, US’183 teaches lymphocyte conditioned media, which is specifically disclosed as being the supernatant derived from activated human lymphocyte cells cultured in growth media. As discussed in the rejection, US’183 also analyzed LCM produced in the disclosed studies and teaches that the LCM comprised a whole battery of soluble mediators including GM-CSF and IL-4, inflammatory cytokines including IL-1β, IL-6, PGE2, TNFα, and IFNγ; chemokines including MCP-1, MIP1, and RANTES, and sCD40L. As such, US’183 does not teach a general composition of conditioned media, as suggested by applicant, but rather specifically teaches a lymphocyte conditioned media that comprised of cytokines/chemokines/growth factors, meeting the instant claim limitation of TITE.
With regards to applicant’s argument that US’183 distinctly teaches that the media is meant for combination with a vaccine antigen, as discussed in detail in the rejections, the instant claims use “comprising” language with regards to the compositions. The specification defines “comprising” as being synonymous with “including,” “containing,” or “characterized by,” and being inclusive or open ended and not excluding additional unrecited elements and/or method steps. The instant specification further indicates that the named elements must be present, but other elements can be added and still form a composition or method within the scope of the presently disclosed subject matter (page 11, lines 7-16). As such, even the inclusion of vaccine antigens still meets the instant claim limitations.
With regards to Wong, applicant argues that Wong does not provide any disclosure regarding the use of the bispecific antibody for the enablement of T cell secretion of the soluble mediators, and T cells are the primary therapeutic in Wong. Applicant argues that this differs from the instantly claimed invention.
As discussed in detail above, the rejection relies on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. Therefore, Wong is not required to teach each and every limitation of the claimed invention in order to establish obviousness. In the rejections, Wong is applied in combination with US’470, to demonstrate that the use of a bispecific antibody to produce the lymphocyte conditioned media of US’183 would have been obvious. As discussed in detail in the rejection, Wong demonstrates that culturing a bispecific antibody in combination with cancer cells and T cells induces T cell activation, proliferation, cytokine secretion, and granzyme B release in a manner that is similar to that occurring with stimulation with anti-CD3/anti-CD28 beads, which is what was used in US’183 to activate T cells. Wong also teaches increases in cytokines/chemokines in cultures that overlap with those of US’183. US’470 is also applied in combination with Wong to support the culturing of bispecific antibodies, T cells, and Cancer cells resulting in increases in other factors, including TNFα, IL-2, and IL-6.
With regards to US’470 (which applicant refers to as “Lindhofer”) applicant argues that, while US’470 teaches the use of activated PBCs and non-viable tumor cells, they do not teach towards anything secreted by either cell of this co-culture as their invented therapeutic, but rather teaches reinfusion of the cells into the cancer patient. Applicant also argues that US’470 teaches the use of T cells from a patient who has cancer while the instant claims specifically recite T cells from a healthy donor.
As discussed in detail above, the rejection relies on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. Therefore, US’470 is not required to teach each and every limitation of the claimed invention in order to establish obviousness. In this case, US’470 is applied to further support the teachings of Wong and the use of bispecific antibodies, T cells, and cancer cells to generate the LCM of US’183. Although the LCM may not be the “invented therapeutic” of US’470 and US’470 may teach T cells from cancer patients, not healthy donors, US’470 is not required to teach either of these limitations as these limitations are met by the teachings of US’183.
With regards to US’823 (referenced by applicant as “Lum”), applicant argues that US’823 does not teach towards the use of healthy T cells to treat cancer patients but rather relies on the use of T cells form oncology patients.
As discussed in detail above, the rejection relies on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. Therefore, US’823 is not required to teach each and every limitation of the claimed invention in order to establish obviousness. In this case, US’823 is applied to demonstrate motivation in the art to substitute bispecific antibodies and T cells with armed activated T cells. Specifically, US’823 teaches that armed activated T cells makes every T cell an antigen-specific CTL and allows the activated T cell to target the cancer cell multiple times, secrete tumoricidal cytokines, secrete chemokines, and survive longer without being rearmed with a bispecific antibody. Additionally, although US’823 may teach T cells from cancer patients, not healthy donors, US’823 is not required to this limitation as the limitation is met by the teachings of US’183.
With regards to US’193 (referenced by applicant as “Fayos”), applicant argues that US’193 teaches a method for submitting a biological sample with platelets and/or leukocytes to different gravitational forces to obtain supernatants with high concentrations of cytokines and coagulation factors. Applicant argues that US’193 does not teach anything regarding priming of cells to secrete potentially therapeutic soluble mediators but rather isolation and concentration methods for naturally secreted factors.
As discussed in detail above, the rejection relies on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. Therefore, US’193 is not required to teach each and every limitation of the claimed invention in order to establish obviousness. In this case, US’193 is applied to demonstrate methods known in the art to concentrate secreted cytokines and coagulation factors resulting in at least 10% compositions by weight and that such methods would be obvious to apply to the LCM of US’183.
Applicant further argues that the rejection asserts that it would have been obvious to forgo using activated and bispecific antibody armed, specifically cancer trained T cells in favor of using the secreted soluble factors present in the media of this co-culture.
The instant rejection, however, does not rely on forgoing the use of the BAT cancer trained T cells in favor of the media of the co-culture, but rather, the use of the BATs disclosed by US’823 in the methods of US’183 to generate the disclosed lymphocyte conditioned media. Additionally, the teachings of alternatives, even preferred alternatives, such as the use of the BAT, does not teach away from the instantly claimed invention, or the combination of applied references, as the teachings of US’823 do not criticize, discourage, or otherwise discredit the claimed solution. See MPEP 2123 (II) which states “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). ‘A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.’ In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)… Furthermore, ‘[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).”
With regards to the reference Rodriguez-Galan and the rejection of claims 14-15 and 32-33, applicant argues that Rodriguez-Galan does not teach that the T cells are constantly secreting miRNAs in response to various stimuli outside of the cell, nor that these miRNA can be inherently leveraged as therapeutic entities. Applicant argues that there is no discussion of miRNA dosing, only of upregulation and downregulation intracellularly in T cells.
It is first noted that the claims do not require that the T cells be constantly secreting miRNAs or any specific dosing of miRNA. The reference Rodriguez-Galan is applied in the rejection to demonstrate that miRNAs, including miRNAs selected from those recited in the rejected claims, were known to be upregulated and expressed during T cell activation and stimulation and that one of ordinary skill in the art would have reasonably expected their presence in the TITE compositions disclosed by the combination of US’183, Wong, US’470, US’823, and US’193.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights