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 .
Application Status
The Response to the Restriction Requirement mailed on November 6, 2025 has been entered. Applicant’s election without traverse of the invention of Group I (claims 1-15 and 20) in the reply filed on November 11, 2025 is acknowledged.
Claims 1-20 are pending in the instant application. Claims 16-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-15 and 20 are under examination herein.
Specification
The disclosure is objected to because of the following informalities:
The specification appears to contain a misspelling of “BALB/c mice” as “BLAB/c mice” at pages 7 and 35.
While the figure numbers for the Drawings have been updated with the Drawings submitted on August 7, 2023, it appears some in-text references to the drawings and/or Examples to which they are relevant were not updated in the amended specification filed on the same date. By way of example, the Brief Descriptions of Figures 25-26 refer to Example 30 (page 9), but the figures are referenced in the text of Examples 28-29 (pages 49-51) as renumbered. The description for Figure 28 references Example 33 (page 9), but Figure 28 is described in the text of Example 31 (page 52). As another example, pages 30-31 of the specification recite that “an embodiment of such control system is provided in Fig. 41” and “An embodiment of the cell irradiator according to the present invention is shown in Figs. 41, and 42A-42D”. However, the renumbered figures only go up to Figure 40, and the figure that previously corresponded to Figure 41 now corresponds to Figure 36.
Appropriate correction is required.
Claim Objections
Claims 1 and 13 are objected to because of the following informalities:
Claim 1 recites that the method comprises “the step of” (singular) in line 2, but goes on to recite multiple steps (plural).
Claim 13 recites, in lines 5-6, “wherein said antibodies are detecting using first induced neoantigens are obtained from tumor cells that have been subject to a survival pressure”. It appears that the “are” (underlined above) is meant to be omitted from the description of the said antibodies.
Appropriate correction is required.
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.
Claim 13 is 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 13 recites the limitation “first induced neoantigens” in line 5 and “second induced neoantigens” in line 8. There is insufficient antecedent basis for these limitations in the claim. While claim 1 (from which claim 13 depends) recites neoantigens in steps (a) and (c), the claim does not specifically articulate “a first induced neoantigen” or “a second induced neoantigen” to which these limitations would have clear antecedent basis.
Further regarding claim 13, the claim recites that antibody titers and lymphocyte transformation are compared in blood samples obtained from the subject before and after step (a) [of claim 1], but neither claim 1 or claim 13 recite blood samples or the step of obtaining blood samples from the subject before and/or after step (a). In addition, the language of the claim does not make clear whether the “tumor cells that have been subjected to a survival pressure” as recited in lines 6 and 9-10 refer to separately obtained tumor cells (from what source?) or to those previously recited in step (c) of claim 1. Accordingly, the steps required for the comparison and assessment cannot be determined and what the purpose of the method of claim 13 cannot be determined because claim 13 fails to particularly point out and distinctly claim the subject matter regarded as the invention.
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.
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 (i.e., changing from AIA to pre-AIA ) 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.
(1)
Claims 1-6, 9, 11-12, 14-15, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Han (WO 2014/075631 A1; original and machine translations attached) in view of Goto (Vaccines (2019) 7(3): 100) and Roger (OncoImmunology (2018) 7(7): e1442166).
Han discloses methods of preparing and administering an autologous tumor vaccine (e.g., Abstract; ¶ 0003). Relevant to claims 1-2 and 14-15, the method of preparing an autologous tumor vaccine comprises the steps of: (1) obtaining isolated autologous tumor cells through surgery or biopsy; (2) treating the autologous tumor cells from step (1) with radiotherapy and/or heating to obtain tumor cells with enhanced antigenicity and antigen presentation; (3) inactivating the tumor cells obtained in step (2) to obtain inactivated tumor cells; and (4) preparing the inactivated tumor cells obtained in step (3) as an autologous tumor vaccine. Han further recites a method of treatment wherein the prepared autologous vaccine is administered to a subject in need thereof to treat a solid or non-solid tumor (e.g., ¶ 0010-0020, 0083-0094; Figure 9; claims 1-2, 9-10, 12-14). (Because the tumor cells are autologous (self-derived), HLA matching is unnecessary. See also Table 1 at page 13 of instant specification.)
Relevant to claim 6, Han recites that the radiotherapy of step (2) may be a particulate radiation (e.g., α, β, γ), optionally selected from the range of 0.10 to 50 Gy and at a dose rate of 0.1 to 10 Gy/min, such as 4-10 Gy at 1.0 Gy/min (e.g., ¶ 0022-0023; Example 1, ¶ 0120-0121; claim 4). Relevant to claim 9, Han teaches that the autologous vaccine comprises an adjuvant such as liposomes or various plant proteins, which enhance the active immune response, reduce negative immune regulation, and enhance immune memory (e.g., Summary, ¶ 0026-0034; claim 8).
Relevant to claim 11, Han teaches a treatment regimen in which the step of detecting tumor residue or metastasis is not performed (and therefore, tumor residue and metastasis are not detected) and wherein the patient is administered the vaccine about 7 days post-surgery (e.g., ¶ 0064-0068). Relevant to claim 12, Han states that “the number of administrations can be 4 courses (3-4 weeks per course) to life” (¶ 0043). Han further recites performing immunological tests to monitor the degree of immune response, such as detection of anti-tumor antibodies or immunoregulatory cell subsets (e.g., lymphocytes) so that immunotherapy can be adjusted as needed (e.g., ¶ 0044-0069, 0095-0100).
Relevant to claim 20, Figure 10 (described in ¶ 0080) illustrates a tumor cell irradiation device that irradiates tumor cells using γ radiation to elicit high expression of oncogenes and enhance the activation and presentation of tumor antigens.
However, Han does not expressly teach administering to the subject an effective dose of a first induction radiation or a low-dose half-course chemotherapy to induce production of neoantigens prior to removing the tumor from the subject in the preparation method (analogous to step (a) in claim 1), alone or in combination with an immunosuppressive blocker.
Goto reviews radiation as an in situ auto-vaccination and a rationale for combining radiotherapy with immunotherapy to treat tumors. Goto teaches that more recent radiotherapy modalities including stereotactic ablative body radiotherapy (SABR; also called stereotactic body radiation therapy or SBRT) have improved anti-tumor response and reduced treatment toxicity (e.g., page 1), relevant to claims 1-2 and 4. Goto further teaches that “radiotherapy induces apoptosis and necrosis in tumor cells, causing them to release tumor antigens, especially neoantigens, into the bloodstream, which may facilitate immune recognition”, thereby overcoming immune escape (pages 5-6). Per Goto, “neoantigens are expressed in cancer cells owing to genomic mutations altering the protein sequence. This type of antigen is tumor-specific and can elicit an immune response sufficient to clear tumor cells when activated” (page 6). Goto discloses that radiation also mediates the translocation of certain endoplasmic reticulum (ER) proteins to the cell membrane before apoptosis, ultimately resulting in the recruitment of effector T cells to the tumor tissue (e.g., pages 6-6; Figure 4). Goto concludes that “the irradiated tumor can become a source of tumor antigens in a process described as in situ auto-vaccination” (page 6).
Goto further describes a phenomenon called the “abscopal effect”, a rare clinical phenomenon in which tumor regression occurs at sites distant from the irradiated region that occurs more frequently in patients co-treated with an immunotherapy such as immune checkpoint blockade inhibitors (e.g., pages 1-3), relevant to claim 5. Selected studies adopting the combination of radiotherapy and immune checkpoint inhibitors are summarized in Table 1 (pages 8-9), including Roger, who tested a regimen of hypo-fractioned radiotherapy with a median total dose of 26 Gy (range 19.5-32.5) administered in 3-5 fractions, which corresponds to approximately 5.2-8.67 Gy per fraction (e.g., Abstract; Results, page 2), relevant to claim 3. Goto further notes that “levels of neoantigens may influence abscopal effects. A high tumor mutational burden (TMB) increases neoantigen levels (Figure 3). Neoantigens released from dying tumor cells increase tumor immunogenicity, which is suggested to prime effector immune cells in the tumor microenvironment. Thus, cancers with higher TMB, rather than those with a lower TMB, release more neoantigens in response to irradiation that potentially intensify abscopal effects” (page 5).
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the autologous vaccine preparation and treatment methods taught by Han by incorporating the additional step of administering a dose of a first induction radiation (alone or in combination with an immunotherapy) prior to excising the tumor tissue and generating and administering the neoantigen vaccine. The skilled artisan would have been motivated to do so because Goto teaches that “in situ auto-vaccination” via radiation (with or without immunotherapy) increases neoantigen production, which may intensify abscopal effects, and increases immune effector cell priming and cytokine release in the subject, thereby amplifying the anti-tumor effect of the treatment. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the ability of the in situ vaccination method (radiation ± immunotherapy) described by Goto for increasing production of neoantigens by the tumor, which would be advantageous for a method of producing an autologous neoantigen vaccine to be administered to the patient.
(2)
Claims 1, 7-8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Han (WO 2014/075631 A1; supra) in view of Goto (Vaccines (2019) 7(3): 100; supra) and Roger (OncoImmunology (2018) 7(7): e1442166; supra) as applied to claims 1-6, 9, 11-12, 14-15, and 20 above, and further in view of Hacohen (US 2016/0339090 A1; cited in IDS).
The teachings of Han are recited in the 35 U.S.C. § 103 rejection above. In addition, pertinent to claims 7-8, Han teaches that an effective dosage of the vaccine of the invention is 0.2-2 μg/kg administered to the individual in need thereof, but also notes that the precise effective dose for a particular subject depends on several factors (e.g., nature and severity of illness, subject’s size, choice of treatment regimen), rendering it “useless to pre-specify the exact effective amount”. Han states that the effective quantity can be determined using conventional experiments (e.g., ¶ 0105-0106). Pertinent to claim 10, Han teaches that the vaccine compositions of the invention may be administered via multi-point intradermal injection (e.g., ¶ 0114-0115).
However, Han does not expressly teach that the autologous vaccine of the invention comprises about 1 mg to about 2 mg of neoantigens and an adjuvant, or that the autologous vaccine is administered by intradermal injection in all four limbs.
The teachings of Goto and Roger are recited in the 35 U.S.C. § 103 rejection above.
Hacohen describes neo-antigen vaccine compositions containing an adjuvant, administered in combination with other agents, for the purpose of treating cancer (e.g., Abstract; ¶ 0011-0018). Hacohen discloses that the neo-antigen vaccines of the invention can be administered in sub-compositions to deliver each sub-composition at or near a draining lymph node (e.g., to each of the arms and legs) of the patient (e.g., ¶ 0012), via intradermal administration (e.g., ¶ 0023), pertinent to claim 10. Hacohen teaches that administration via the lymph nodes reduces toxic systemic exposure and maximizes treatment effectiveness of the co-administered immunotherapy (e.g., ¶ 0606). Pertinent to claims 7-8, Hacohen further discloses that the neo-antigen vaccine is administered at a dose of about 10 μg to 1 mg per 70 kg individual as to each neoantigenic peptide (e.g., ¶ 0030-0036).
In view of the further teachings of Hacohen, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at an autologous vaccine preparation and treatment method as collectively set forth by Han, Goto, and Roger, wherein the vaccine comprises about 1 mg to about 2 mg of neo-antigens and is administered via intradermal injection in all four limbs of the subject, through the process of routine optimization. The skilled artisan would have been motivated to do so because neo-antigen vaccines have utility in treating cancer, and optimizing the treatment dose ensures that the treatment is effective for the greatest number of people. There would have been a reasonable expectation of success because the anti-tumor vaccines described by Han et al. and by Hacohen share equivalent functions and are used for the same purpose, and it is prima facie obvious to substitute equivalent compositions known for the same purpose.
With regard to the specific dosage and interval amounts recited in the instant claims, "[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 see M.P.E.P. § 2144.05 (II)(A). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that dosage and treatment interval optimization is obvious.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643