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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/23/2026 has been entered.
Claims 2, 4-5, 12-13, 16-18, 20, 22-23, 30-31, 34, and 36-52 are cancelled and claims 62-64 are new. Claims 1, 3, 6-11, 14-15, 19, 21, 24-29, 32-33, 35, and 53-64 are currently pending and are examined on the merits herein.
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.
Withdrawn Rejections
Claims 1, 3, 6-11, 19, 21, 24-29, 35, 53-57, and 58-61 were rejected under 35 USC 103 over US’470, US’823, US’183, and US’193. The rejections are withdrawn in favor of the modified rejections below.
The following objections and rejections are new.
Nucleotide and/or Amino Acid Sequence Disclosures
The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing in the specification. See item 1) a) or 1) b) 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 Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 62-63 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 62 depends on the method of claim 1 and recites the limitation “wherein the composition provides a cytotoxicity of at least 20%”. Claim 1 recites a method for treating cancer comprising administering to a subject an effective amount of a cell-free composition as recited. Claim 1 uses “comprising” language with regards to the method of treatment indicating that the administration of additional, unrecited elements in addition to the cell-free composition recited would still meet the claim limitations. As claim 62 references “the composition” as providing the recited cytotoxicity, it is unclear if the intention of the claim is to limit the method of claim 1 to comprising administration of only the recited cell-free composition or if any embodiment of the method, which includes additional, unrecited elements, resulting in at least 20% cytotoxicity would meet the instant claim limitations. As such, the metes and bounds of the claim are indefinite.
Appropriate correction/clarification is required.
In the instant office action, the limitation of claim 62 is interpreted as applying to the method of claim 1 wherein the method comprising administration of the claimed composition results in the recited cytotoxicity of at least 20%.
Claim 63 depends on the composition of claim 19 and recites the limitation “wherein the composition provides a cytotoxicity of at least 20%. Claim 19 recites a pharmaceutical composition comprising, consisting essentially of, or consisting of an effective amount of a cell-free composition as described. Claim 19 does not include any intended use for the composition or the treatment of any type of disease or condition that the claim to cytotoxicity of at least 20% could be referring to. Therefore, the limitation in claim 63 lacks antecedence as there is no recitation to which the cytotoxicity could be applied.
Appropriate correction/clarification is required.
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.
Claims 1, 3, 6-11, 14-15, 19, 21, 24-29, 32-33, 35, and 53-64 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 62-64, new claims 62-64 depend on claims 1, 19, and 35, respectively and recite the limitation that the composition provides a cytotoxicity of “at least 20%”. There is insufficient support for the recited limitations in the originally filed disclosure and the claim to such is identified as new matter.
The originally filed disclosure does not contemplate a minimum percent cytotoxicity that must result from, or be provided by, the claimed methods and compositions nor does the disclosure specifically disclose at least 20% cytotoxicity.
The response cites Example 8 and Fig. 1I as supporting the new limitations. In example 8, TITE were examined for their effects on various tumor cell lines. Effects of various doses (5%, 10%, and 25%) B-CM or TITE on tumor cells including SKBR3, MB231, MiaPaCa-2, L3.6p1, CoLo-356, A431 and H292. Results are reported in Fig. 1I. The example discloses 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. It was confirmed that the TITE mediated cytotoxicity in a large number of cell lines from various tumor types. 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 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).
While the results do demonstrate some results in which the cytotoxicity is above 20%, there is no indication in the example, figure, or remainder of the disclosure that a cytotoxicity of at least 20% was considered as a threshold or minimum cytotoxicity required.
As it is not evident from the originally filed disclosure that applicant had considered a threshold of at least 20% cytotoxicity resulting from the claimed methods and compositions, one of ordinary skill in the art would not reasonably recognize that applicant was in possession of the instant claims at the time of the effective filing date of the claimed invention. As such, the claims were identified as being drawn to new matter.
Regarding claims 1, 3, 6-11, 14-15, 19, 21, 24-29, 32-33, 35, and 53-64, independent claims 1, 19, and 35 encompass a genus of methods/compositions and recite functional limitations, such as the use of the methods/compositions for the treatment of cancer. The claims also recite functional limitations requiring the methods/compositions to provide at least 20% cytotoxicity (see claims 62-64).
Specifically, claim 1 is drawn to a method of treating cancer in a subject comprising administering to the subject an effective amount of 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.
Claim 19 is drawn to a pharmaceutical composition comprising, consisting essentially of, or consisting of, an effective amount of a cell-free composition comprising at least 10% by weight TITE derived from a culture comprising a BAT and a cancer cell, wherein the activated t cell is derived from a T cell of a healthy donor.
Claim 35 is drawn to a method of preparing a composition for treating cancer, the method comprising culturing BATs, where the activated T cells are derived from a T cell of a healthy donor, and cancer cells to provide a culture comprising a complex comprising cancer cells and ATC, wherein one binding domain of the BiAb in the BAT binds to an antigen on the T cells and the second binds an antigen on the cancer cells; and isolating cell-free media from the culture, wherein the media comprises BAT induced TITE, to thereby provide a composition comprising at least 10% by weight TITE for treating cancer.
New claims 62-64, which depend on claims 1, 19, and 35, respectively further recite the functional limitation that the composition provides a cytotoxicity of “at least 20%”.
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 (page 57, line 30 – page 58, line 1), suggesting that released components are considered TITE.
As such, the claims are drawn to a genus of methods/compositions which are limited by the recited functional limitations.
Specifically, the claims encompass the treatment of any type of cancer, with compositions comprising any material that could be considered to be a Tumor-targeting effector so long as the amount of TITE in the composition is at least 10% by weight and are generated using a BAT and any type of cancer cell, and administered by any route. Additionally, the claims encompass any therapeutically effective amount of the compositions for the treatment of the cancer. This is particularly the case as the recitation in the claims regarding the compositions comprising at least 10% by weight of TITE is the amount that must be in the composition, but does not necessarily impact the amount of TITE that is administered to a subject to treat cancer. It is also noted that the claims encompass compositions of TITE only and methods in which these compositions are the only thing administered to a patient for the treatment of cancer which also encompasses cytotoxicity of at least 20%.
As such, the claims are drawn to a genus of methods/compositions which are limited by the functional recitations of treating cancer and providing a cytotoxicity of at least 20%.
The instant disclosure, however, does not provide a representative number of species performing the claimed functions 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 examples of the instant disclosure detail 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 doses (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 not clear from the example how the doses of 5%, 10%, and 25% were calculated or what 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 concentration 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. It was confirmed that the TITE mediated cytotoxicity in a large number of cell lines from various tumor types. 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 results do demonstrate that, under the tested conditions and compositions, treatment of some cancer cell lines with TITE result in cytotoxicity, including cytotoxicity that is at least 20%. However, the results also demonstrate 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 HN12 showed no killing by controls or TITE compositions. Additionally, if the % values reported represent the % by weight TITE, Fig. 1I demonstrates that, with 10% TITE, at whatever amount was administered, tumor models L3.6 and CoLo 356 both had less than 20% cytotoxicity.
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).
The examples demonstrate the claimed functions in only particular cancer cell lines, with a single TITE composition with varying ranges of total TITE comprised therein that was derived from cultures comprising BATs and only a single cancer type and administered via IV. Additionally, it is unclear what the exact TITE composition that provided the results comprised.
As such 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%.
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 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).
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, 3, 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). US’183 demonstrates in Fig. 5A 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 cancer cells as 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 bene 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 mammary 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 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 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 02/23/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that the rejection is inappropriately applying hindsight in advancing the rejection. Applicant argues that one of ordinary skill in the art would not combine the teachings of US’193 (referenced by applicant in the response as “Vidal Fayos”) with the other applied references. Applicant argues that there is no teaching in US’193 that the composition could be employed in the treatment of cancer, but rather describes serums or fibrin gels that could be considered in the treatment of a disease or pathology. Applicant argues that cancer is not mentioned in US’193.
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, the rejections rely on the combination of applied references and what the references would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. As such, US’193 is not required to teach the treatment of cancer as the treatment of cancer using supernatant comprising TITE is taught by the combination of US’183, Wong, US’470, and US’823. Rather, US’193 is cited in the rejection to demonstrate that methods were known in the art to concentrate supernatants to have high concentrations of cytokines and coagulation factors, including TNF-α, IL-6, and IL-1β, which are suggested by the combination of applied references. US’193 also demonstrates that compositions comprising at least 10-30% w/w of the effectors can be obtained and, in the studies disclosed, it is demonstrated that compositions with these concentrations can be used to elicit cellular responses.
Furthermore, it noted that the instant claims do not require any specific amount of the composition be delivered for the treatment of cancer, rather the claims only require that the composition comprise at least 10% by weight TITE. As such, in the broadest reasonable interpretation of the claims, any amount of the composition could be administered for the treatment of the cancer as long as the composition itself comprises at least 10% weight of the TITE.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693