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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-9 have an effective filing date of 06/09/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9 June 2022, 18 September 2023, and 10 March 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
Claims 1, 5, and 8 are amended. Claims 10-13 are new. Claims 1-13 are pending and under examination
Response to Remarks filed 11/13/2025
Regarding the objection to claim 5, Applicant’s arguments and amendments have been fully considered and are persuasive. Deleting epitome and inserting epitope overcomes the objection.
Regarding the 35 USC 102 rejection, Applicant’s arguments and amendments have been fully considered and are not persuasive.
Applicant states, “Claims 1, 2, 5, 6, and 8 stand rejected under 35 U.S.C. 102(a)(1) as being anticipated by Boudousquie et al. Applicant respectfully disagrees as Boudousquie fails to disclose, inter alia, the features of "mechanically pulverizing the frozen malignant tissue sample" and "injecting the mechanically pulverized malignant tissue sample into said patient" as instantly claimed. Instead, what Boudousquie injects into the patient are dendritic cells that have been processed and incubated with tumor lysate (the OC-DC vaccine), not the mechanically pulverized, frozen malignant tissue sample itself.
The Claimed Invention Directly Injects the Mechanically Pulverized Frozen Tissue Sample
Claims 1, 2, 5, 6, and 8 are directed to a method of inducing an immune response in a patient that includes biopsying a malignant tissue sample from a patient, freezing the malignant tissue sample to produce a frozen malignant tissue sample, mechanically pulverizing the frozen malignant tissue sample, and injecting the mechanically pulverized malignant tissue sample into the patient. Thus, the claimed method is a simple four-step process: acquire, freeze, pulverize, inject. There are no chemical manipulation steps, no cryopreservation steps, no dendritic cell culture, no loading of tumor lysate onto dendritic cells, and no maturation of dendritic cells. The mechanically pulverized tissue sample itself-not cells loaded with the tissue sample-is what is injected into the patient.
The GentleMACS is a Gentle Agitator; Not a Mechanical Pulverizer
The Examiner characterizes the GentleMACS as "a mechanical pulverization" system. However, the GentleMACS device is specifically designed to preserve and separate viable cells through gentle agitation, not to mechanically pulverize tissue. The GentleMACS apparatus requires the soaking and agitation of thawed samples to optimally separate viable cells from tissue samples. Boudousquie's process involves processing tumor fragments into small fragments (approximately 1-3 mm3) that are used fresh or thawed following cryopreservation into 90% Human serum and 10% DMSO, with dissociation performed using RPMI 1640 supplemented with DNase I and collagenase followed by incubation on the GentleMACS. The use of cryopreservation media (90% Human serum and 10% DMSO) and the enzymatic treatment (DNase I and collagenase) demonstrates that Boudousquie's process is designed to isolate viable cells, not to mechanically pulverize tissue into a nonviable slurry. In contrast, embodiments of the instant method include freezing the malignant tissue sample to about -78.5°C to about -196°C by exposure to liquid nitrogen, which rapidly freezes the sample, resulting in destruction of cell membranes and killing all cells in the malignant tissue without preservation. The mechanical pulverization utilizes mechanical means to pulverize the frozen and hard malignant tissue sample instead of traditional cell-based means that require post- extraction processing. The mechanical pulverization of the tissue sample produces a pulverized frozen nonviable malignant tissue sample which maintains native cellular protein structural integrity while facilitating the exposure of any and all cancerous epitopes. This requires immediate mechanical disruption after rapid freezing without any chemical denaturing of the sample. The GentleMACS would not work for the claimed method because it is designed for gentle cell separation, not mechanical pulverization: two distinct processes.
Boudousquie Does Not Disclose Mechanical Pulverization While Frozen
The Examiner asserts that "it is further noted that Boudousquie et al does not mention thawing the cryopreserved sample prior to disassociation. Therefore, it would have been frozen at the time of mechanical pulverization." However, Boudousquie explicitly discloses that dissociation is performed using RPMI 1640 supplemented with DNase I and collagenase followed by an incubation on the GentleMACS using a tumor dissociation of three cycles of 30 min at 37 °C. The incubation at 37 °C indicates that the sample would be thawed during this process, not mechanically pulverized while frozen as required by the claims. (Cf. Independent claim 1, which recites "mechanically pulverizing the frozen malignant tissue sample") ”
However, Boudousquie et al teach that the frozen malignant tissue is mechanically pulverized utilizing the GentleMACS system (Boudousquie et al, pg. 2-3, paragraph 2.2). Additionally, Boudousquie et al teach injecting the tissue sample after mechanical pulverization into a patient (Boudousquie et al, pg. 15, paragraph 2). It is noted that injection is a route of administration. It is further noted that Boudousquie et al does not mention thawing the cryopreserved sample prior to disassociation. Therefore, it would have been frozen at the time of mechanical pulverization.
The GentleMACS system includes blades for mechanical pulverization. Therefore, it is a mechanical pulverization tool. Furthermore the specification does not specifically define what constitutes mechanically pulverized tissue, only indicating that mechanical pulverization of tissue exposes epitopes – “[0031] After freezing the malignant tissue sample, the sample is mechanically pulverized by a crusher, e.g., a sterile crusher. The mechanical pulverization utilizes mechanical means to pulverize the malignant tissue sample instead of traditional chemical means. The mechanical pulverization of the tissue sample produces a pulverized malignant tissue sample which results in the pulverized tissue sample exposing epitopes. That is, the frozen tissue sample is mechanically pulverized until epitopes are exposed.” Given that the GentleMACS system uses blades to blend or homogenize tissue, tissue that is processed by the GentleMACS system would be expected to have exposed epitopes and thus meet the broadest reasonable interpretation of the phrase “mechanically pulverized tissue.” The GentleMACS system does not require thawing of the samples. The samples may thaw during the process, similar to the instantly claimed invention wherein the samples would begin to thaw during the process of mechanical pulverization even if frozen at the start of the mechanical pulverization process. Therefore, the GentleMACS would work for the process as claimed.
While the claimed invention may not include some of the steps described in Boudousquie et al, instant Claim 1 states that the invention is comprising of the instantly claimed steps, allowing the inclusion of other steps in the process.
Regarding claim 13, Boudousquie et al teach cell viability was assessed after processing (Boudousquie et al, pg. 4-5, paragraph 3.1).
Therefore, Boudousquie et al meets the limitations of claims 1, 2, 5, 6, and 8, 10, and 13. Therefore, the 35 USC 102 rejection is maintained.
Previous Rejections Maintained- Nonfinal Rejection 05/14/2025
35 U.S.C. 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 5, 6, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Boudousquie et al. (Boudousquie et al, Vaccines 2020, 8, 25, publication date: 01/14/2020).
Boudousquie et al teach that tumor samples taken from a patient can be cryopreserved then disassociated using the GentleMACS (a mechanical pulverization) system after which it is put in DPBS, a solvent (Boudousquie et al, pg. 2-3, paragraph 2.2). Boudousquie et al further teach that after the tumor sample can be injected into a patient in combination with dendritic cells (Boudousquie et al, pg. 15, paragraph 2).
It is further noted that Boudousquie et al does not mention thawing the cryopreserved sample prior to disassociation. Therefore, it would have been frozen at the time of mechanical pulverization.
Therefore, Boudousquie et al teach a method of inducing an immune response in a patient by biopsying a malignant tissue sample from a patient, freezing the malignant tissue sample to produce a frozen malignant tissue, mechanically pulverizing the frozen malignant tissue sample, mixing the mechanically pulverized sample into a solvent, and injecting that sample into the patient, therefore meeting the limitations of claims 1 and 2.
With respect to claims 5, 6, and 8, it is noted that mechanical pulverization of the tissue sample inherently results in the exposure of epitopes.
Therefore, all of the limitations of claims 1, 2, 5, 6, and 8 are met by Boudousquie et al.
Regarding the 35 USC 103 rejection, Applicants arguments and amendments have been fully considered and are not persuasive. Applicant states, “Boudousquie Does Not Teach Injecting the Mechanically Pulverized Tissue Sample” and “Hopkins Does Not Remedy the Deficiency in Boudousquie”.
However, as discussed above Boudousquie et al teach injection of the mechanically pulverized tissue sample. As shown in Figure 7, the samples can be injected into the patient after tumor lysate is removed through phenotyping as well as with both the tumor lysate and dendritic cells.
Furthermore, Hopkins teaches the freezing with liquid nitrogen and crushing with mortar and pestle (mechanical pulverization). It is noted that freezing with liquid nitrogen is a method of rapidly freezing. It is further noted that freezing with liquid nitrogen brings the tissue sample down to a temperature of about -78.5 to about -196C as an inherent feature of the process.
Therefore the invention of Boudousquie et al and Hopkins et al meet the limitations of claims 1-13. Therefore, the 35 USC 103 rejection is maintained.
35 U.S.C. 103
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.
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.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Boudousquie et al. (Boudousquie et al, Vaccines 2020, 8, 25, publication date: 01/14/2020), in view of Hopkins (Hopkins, Labcompare Selected Products 2020, 565667, 1-12, publication date: 06/25/2020).
As indicated above Boudousquie et al teach a method of inducing an immune response in a patient by biopsying a malignant tissue sample from a patient, freezing the malignant tissue sample to produce a frozen malignant tissue, mechanically pulverizing the frozen malignant tissue sample, mixing the mechanically pulverized sample into a solvent, and injecting that sample into the patient.
Boudousquie et al do not teach the method of inducing an immune response of claim 1, wherein the step of freezing the malignant tissue sample comprises freezing the malignant tissue sample with liquid nitrogen, the method of inducing an immune response of claim 1, wherein the step of mechanically pulverizing the frozen malignant tissue sample comprises crushing the frozen malignant tissue sample via a crusher tool. This deficiency is remedied by Hopkins.
Hopkins et al teaches that the classic cryogrinder is a ceramic mortar and pestle (a crusher tool) precooled to dry ice or liquid nitrogen temperatures (Hopkins et al, pg. 4, only paragraph). Hopkins et al further teaches that samples can be frozen with liquid nitrogen, and that its use is mostly a matter of common sense (Hopkins et al, pg. 8, last paragraph).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Boudousquie et al with those of Hopkins to arrive at method of inducing an immune response of claim 1, wherein the step of freezing the malignant tissue sample comprises freezing the malignant tissue sample with liquid nitrogen, the method of inducing an immune response of claim 1, wherein the step of mechanically pulverizing the frozen malignant tissue sample comprises crushing the frozen malignant tissue sample via a crusher tool. One of ordinary skill in the art would have been motivated to do so, because Boudousquie et al teach that tumor samples taken from a patient can be cryopreserved then disassociated using the GentleMACS system after which it is put in DPBS, a solvent. Boudousquie et al further teach that after the tumor sample can be injected into a patient in combination with dendritic cells. Furthermore, based upon the teachings of Hopkin, one of ordinary skill in the art would have been motivated to use the method of cryopreserving malignant tissue samples with liquid nitrogen and mechanically pulverizing by cryogrinding with a mortar and pestle as the process is considered simple and low cost (Hopkins et al, pg. 4, only paragraph). As such one skilled in the art would have been motivated to modify the invention of Boudousquie et al, which teaches the processing of cryopreserved tumor biopsy by mechanical pulverization which is mixed into a solvent and administered to patients to further include the cryopreservation of the tissue using liquid nitrogen and mechanical pulverization with a mortar and pestle (crusher tool), because there would have been reasonable expectation that the resultant invention, which comprises, a method of preparing a tumor vaccine that involves the preparation of the tissue sample by cryopreserving with liquid nitrogen and pulverizing the frozen sample with a mortar and pestle, is effective in producing a malignant tissue sample that can be injected into a patient. Boudousquie et al and Hopkins meet the limitation of instant claims 1-8.
With respect to claim 9, Boudousquie et al further teaches that the process of acquiring tissue, processing, and injecting into the patient must be sterile (Boudousquie et al, pg. 11, figure 7). It is obvious to use an extraction tool to extract tumor tissues and subsequently place them in a container as it is routine in the art and one skilled in the art would be motivated with a reasonable expectation of success to perform biopsies by using an extraction tool and placing the extracted tissue in a container because it is routine in the art. Boudousquie et al further teaches that the tissue sample is injected with a syringe (Boudousquie et al, pg. 15, paragraph 2, #5). One skilled in the art would be motivated with a reasonable expectation of success to keep the tools they used in the combined teachings of Boudousquie et al and Hopkins sterile in order to maintain the sterility of the sample as required by Boudousquie et al. Furthermore, one of ordinary skill in the art would recognize the need to keep a therapeutic injection sterile, in order to avoid infection of the patient. Therefore, the tools disclosed are necessary and inherent to carry out the processes of Boudousquie et al and Hopkins disclosed above. Neither Boudousquie et al or Hopkins disclose the creation of a kit with the tools. However, it would be obvious to put the tools of Boudousquie et al and Hopkins in a kit to perform the same functions they perform in the disclosed references, such as the one described in instant claim 9, as one would have reasonable expectation of success that the tools in the kit would continue to perform their functions even after placement in a kit. Additionally, one skilled in the art would be motivated to create a kit as it is convenient to have all of the tools in one place.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references cited.
Conclusion
THIS ACTION IS MADE FINAL. 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.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE K DARPOLOR whose telephone number is (571)272-0115. The examiner can normally be reached 7:30ET-4:30ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642