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 provisional application 63359735, filed on 07/08/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
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 9 and 21 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.
Claims 9 and 21 require culturing cancer cells in a medium containing a growth factor to increase the expression level of a specific marker in the cells prior to the coculturing step.
Upon reviewing the specification, in view of the presented claims, the specification shows that Applicants have not provided sufficient description of all the growth factors that would be used to induce the expression level of specific markers. The specification does not even provide sufficient description of which growth factor to be used to induce which marker. The specification states that “ The cancer cells are grown in the presence of known growth factor as supplements ( e.g., epidermal growth factor, insulin, or insulin-like-growth factor, depending upon the cell-type) which are known to induce the expression level of the markers” but does not specify which markers would be induced by using the exemplified growth factors or the candidate cancer cell types. The specification also does not provide sufficient information of the type of cancer cells that would be used in such a system to produce predictable results. Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998).
The claim recites the structure (e.g. growing cancer cells in a medium containing a growth factor) has function (e.g. induce the expression level of a specific marker). There is no data to show which growth factor should be utilized on which cancer cell type to induce the expression of what marker. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. It is apparent that applicants do NOT have possession of growing any cancer cell type in a medium containing any growth factor that would induce the expression of any marker. Consequently, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
Claim Rejections - 35 USC § 112
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 9 and 21 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.
Regarding claims 9 and 21, the claims recite that “ when at least about 90% or at least about 80% of the cancer cells do not exhibit the level”. The phrase is vague, and it is unclear to what exactly Applicants are referring. For examination purposes, the office interprets the claims to mean that “when at least about 90% or at least about 80% of the cancer cells do not exhibit the level of expression for a specific marker, the cancer cells are growing in the presence of a growth factor that is known to induce the expression level of the specific marker”. Appropriate correction and clarification is required.
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.
Claims 1-29 are rejected under 35 U.S.C. 103 as being unpatentable over Imam et al ( US 2018/0275027 A1), in view of Kastner et al ( Molecular Cancer Research, 2012), and Schmiegel et al (PNAS, 1992), as evidenced by Simon et al ( Bio techniques, 2016) .
Regarding claim 1, Imam et al disclose a method for making synthetic tissue controls (STC) and synthetic tissue microarray controls (STMC) for immunohistochemical (IHC) and in situ hybridization (ISH) testing for cancer diagnosis and prognosis. Imam et al also provide methods for determining presence of one or more types of cancer. (Paragraph [0003]). Imam et al disclose that STMC is constructed to include a plurality of types of cancer cells with varying levels and patterns of expression of markers of interest, this reads on selecting cancer cells with a known positivity or negativity for a specific marker. (Paragraph [0042]). Imam et al also teach that the method of constructing the STC and STMC involves coculturing cancer cells and stromal cells in a plurality of cell culture bags, with the cell culture bag being mounted on a bioreactor in a CO2-incubator during the co-culturing process (Paragraphs [0005], [0030]), this reads on steps 4-5 of instant claim. According to Imam et al, the coculturing process is held in an approximately zero gravity environment for a period of eight to twelve days (Paragraphs [0031). Imam et al also teach utilizing a motorized rotating device to slowly spin the cell culture chambers at a speed to allow the cells to develop characteristics similar to or identical to characteristics of actual tumor tissue (Paragraphs [0031). Clearly, the method of Imam et al involves culturing cells in nonadherent condition, for example in suspension, which promotes spheroid formation. Imam et al further suggest that fibronectin may be added to the medium at the first day of coculturing. According to Imam et al, adding fibronectin to the coculture facilitates formation of basement membrane-like structures during an early phase of growth of the co-culture cells, facilitating the co-cultured cells to resemble actual tumor, and improves the contact between the co-cultured cancer cells and the normal stromal cells. The statement that the presence of fibronectin in a rotary bioreactor facilitates the co-cultured cells to resemble actual tumors, further suggest that the culturing process of Imam et al produces spheroids comprising of a mixture of cells. Imam et al further teach harvesting, fixing, and embedding the fixed cocultured cells in a paraffin block core (Paragraphs [0027], [0038], and Fig.1, and Fig.2D-wherein the 204 represent the cocultured cells deposited in the core of the block), this reads on steps (6-8).
Imam et al do not teach growing cancer cells to a phase (i.e. the second step); nor do they teach screening the cancer cells in the phase for expression of a specific marker (i.e. the third step).
Kastner et al demonstrate that the mRNA encoding orphan G protein-coupled receptor 19 (GPR19) is frequently overexpressed in tissue samples obtained from patients with small cell lung cancer (SCLC) (See abstract, and Fig.1). Kastner et al further demonstrate that the expression levels of Gpr19 mRNA varied along the cell-cycle with a peak observed in S-phase (See abstract, and Fig.6). Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify Imam et al with the teaching of Kastner, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. One would be motivated to grow the cancer cells to a specific cell-cycle phase, knowing that the expression level of some markers would change as the cell-cycle progressed. There is a reasonable expectation of success to grow cancer cells to a specific phase prior to the coculturing step because doing so would provide various cancer cells with different expression level that can be used as a reference control for cancer diagnosis.
Regarding claims 2-4,6,8, and 18-20, following the discussion of claim 1 above, Imam et al in view of Kastner et al render obvious growing cancer cells to a specific cell-cycle phase to provide cancer cells with various expression level of a specific marker. As previously noted, Imam et al disclose that STMC is constructed to include a plurality of types of cancer cells with varying levels and patterns of expression of markers of interest.(Paragraph [0042]). Imam et al further state that “STC and STMC may be cultured to consistently provide various levels of expressions of biomarkers”, and suggest utilizing immunohistochemical (IHC) staining to detect the expression level of a specific marker in the cocultured cells (See paragraph [ 0035]). Neither Imam nor Kastner explicitly state that the cells should be grown to a phase in which the phase has positivity or negativity for the specific marker, or to a phase where at least 90% of the cells exhibit the level, etc. However, determining a phase where the cells either express a specific marker or do not, discovering an optimal % of cells that express a specific level of expression of biomarkers, or determining the level of expression being high, medium, or negative, these are all claim limitations that are well-understood, routine, and conventional steps in the relevant art. Therefore, one with ordinary skill in the art would be motivated to use routine experimentation to discover an optimum value of a result. The motivation of doing so would be to include various cancer cells with different expression level that can be used as a reference control for cancer diagnosis. One of ordinary skill in the art would be able to arrive at the limitations recited in instant claims through routine experimentation.
As per the MPEP. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219(C.C.P.A. 1980). See MPEP 2144.05.
Regarding claims 5 and 7, the combined teachings of Imam and Kastner render obvious growing the cancer cells to a phase prior coculturing. Imam et al further state that “ the STC and STMC are cultured to provide high expression (HE or 3+) of biomarkers used in IHC and ISH staining. In other embodiments, STC and STMC are cultured to have medium expression (ME or 2+) of biomarkers used in IHC and ISH staining. In further embodiments, STC and STMC are cultured to have low expression (LE or 1 +) of biomarkers used in IHC and ISH staining”. (See paragraph [0035]).
Regarding claims 9 and 21, Imam et al teach culturing cancer cells, such as MCF-7, in the presence of insulin to promote the cancer cell proliferation prior to the mixing step (See paragraph [0032]). However, Imam et al do not teach culturing cancer cells prior to the mixing step in growth-factor containing media to increase the expression level of a specific marker in the cancer cells.
Schmiegel et al demonstrate that growing pancreatic carcinoma cells in a medium containing recombinant human tumor necrosis factor (TNF)-a increases the expression of epidermal growth factor receptor (EGFR) at the mRNA and protein level. In addition, Schmiegel et al demonstrate that treating pancreatic cancer cells with TNF-a increases the expression of an EGFR ligand, transforming growth factor (TGF)-a, at the mRNA and protein level in all cell lines. (See abstract).
Taken together, the teachings of Imam et al in view of Schmiegel et al render obvious claims 9 and 21, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Imam et al teach a method of making a tissue reference block comprising of co-cultured mixture of normal and cancer cells, but fail to suggest growing the cancer cells prior to the coculturing step in a medium containing growth factor to increase the expression level of a specific marker. Schmiegel et al teach that culturing pancreatic cancer cells in a medium comprising (TNF)-a increases the expression level of EGFR and TGF-a. Therefore, an ordinary skill in the art who had reviewed Imam et al could have come across Schmiegel and immediately noticed the possibility of growing cancer cells of Imam et al in a medium containing a growth factor to increase the expression of a specific marker that can be used in diagnosis. There is a reasonable expectation of success, when making a tissue reference block, to culture the cancer cells of Imam et al in a medium containing a growth factor because doing so would provide cells that express a specific marker that can be used in cancer diagnosis.
Regarding claims 10-12, and 22-24, the method of Imam et al involves coculturing the mixture of cells for about 10 days ( See paragraph [0030]), this reads on claims 12 and 24. Imam et al also state that “ In some embodiments, approximately 80 million stromal cells and/or
cancer cells may be harvested from each cell culture bag after approximately ten days of co-culturing”. Imam et al do not explicitly disclose the ratio or the relative number of normal to cancer cells in the mixture. However, these limitations are also routine in the art and one with ordinary skill in the art at the time the invention was filled would be motivated to use routine experimentation to determine the optimal number or ratio of cells to produce spheroids that resemble the actual tumor tissue.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05.
Regarding claims 13,16, 25, and 28, Imam et al do not teach cutting a segment from the core and placing it in a recipient block, nor do they teach cutting the entirety of one of the recipient blocks into sections. However, these limitations are common practice in the relevant art as evidenced by Simon et al. Simon et al teach a method of preparing a recipient tissue microarray. The method involves transferring a segment of paraffin-embedded tissue from a donor block into a recipient block to construct a recipient block consisting of a paraffin tissue microarray ( See Fig.1). Simon et al also teach cutting the recipient blocks into sections and staining it for the presence of specific markers (See Fig.2). Simon et al state that constructing a tissue microarray (TMA) allows for sections from the TMA blocks to be used for simultaneous in situ analysis of hundreds to thousands of tissue samples (See section “Tissue Microarray Technology” on page 98, 2nd column). Therefore, instant claims are combining prior art elements according to known methods to yield predictable results, namely the predictable result is to construct a tissue microarray comprising of patients tissue samples and tissue reference control block of claim 1. Imam et al in view of Kastner et al render obvious constructing tissue reference control block comprising of co-cultured cancer and normal cells. Simon et al teach a method for constructing a tissue microarray and clearly suggest that the TMA can be used to facilitate the simultaneous analysis of thousands of tissue samples. An ordinary skill in the art would be motivated to combine the teachings of Imam and Simon to generate a TMA comprising of patients samples and the reference control block of Imam et al because doing so would facilitate the analysis of many patient tissue samples at the same time.
Regarding claims 14-15, 17,26-27, and 29, Imam et al teach utilizing a recipient block
consisting of a paraffin tissue microarray (See paragraph [0059] ), this reads on claims 14 and 26. The method of Imam et al also involves cutting the paraffin blocks into sections and testing them to determine the presence of various markers used in pathology testing laboratories (See paragraph [0027] ), this reads on claims 15,17, 27, and 29.
Conclusion
No claim is allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638