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 (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.
Priority
This application claims priority to the U.S. National Stage (371) application of PCT/US2019/063977 filed on 12/02/2019 which claims priority to U.S. Provisional Application No. 62/774,177 filed on 12/01/2018.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Provisional Application No. 62/774,177, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The prior-filed application does not provide support for limitation “serum free media comprising low-density lipoproteins” in claim 1. Although this limitation was part of the original specification in the current application and in the specification of the U.S. National Stage (371) application of PCT/US2019/063977, the specification and claims of the prior-filed provisional application do not disclose the limitation “serum free media comprising low-density lipoproteins”.
Accordingly, claims 1, 3-6, 10-11 and 13-23 are not entitled to the benefit of the prior provisional application No. 62/774,177 and are only entitled to claim priority to the U.S. National Stage (371) application of PCT/US2019/063977 filed on 12/02/2019.
Thus, for the reasons above, the claims currently have an effective filing date of 12/02/2019.
Claim Status
Claim 1 is previously presented. The Applicant amended claims 13 and 23 and notes that no new matter is added. The Applicant cancelled Claims 2-3, 7-9 and 12. Claims 4-6 and 10-11 and 14-22 are original.
Thus, claims 1, 4-6, 10-11 and 13-23 are pending and are under examination.
Maintained Rejections
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 (PHOSITA) 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, 4-6, 13-14, 16, 18-20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2018/064440 A1), Sabatini et al. (WO 2018/089928 A1), Kovář et al. (Methods in Enzymology, Vol. 121, 277-292), Huang et al. (US 2012/0316137 A1) and StemCell Technologies (Catalog# 09500, 2017).
Regarding claim 1, Lee teaches a method for assessing sensitivity of multiple myeloma cells obtained from a subject to chemotherapeutic agents in an ex vivo assay (Abstract).
Lee teaches that wherein the multiple myeloma cells obtained from the subject are cellular components of a bone marrow aspirate from the subject (Page 89, [000428]).
Lee teaches contacting the multiple myeloma cells obtained from the subject with at least one chemotherapeutic agent ex vivo (Page 33, [000117]).
Lee teaches incubating the multiple myeloma cells with the at least one chemotherapeutic agent to form incubated cells (Page 91, [000435]).
Lee teaches that wherein the incubating further comprises contacting the cells with interleukin-6 (IL-6) (Page 27, [000106]).
Lee teaches labeling at least one protein selected from the group consisting of CD 138, CD38, CD45, and CD19, on the surface of the incubated cells to form labeled multiple myeloma (MM) cells (Page 37, [000128] and [000132]).
Lee teaches analyzing the labeled MM cells by flow cytometry to determine the sensitivity and resistance of the subject's multiple myeloma cells to the at least one chemotherapeutic agent (Page91, [000435]).
Lee teaches how to incubate bone marrow mononuclear cells (BMMC) for one hour or for 24 hours after adding a therapeutic agent (Page 102, [000468]).
Regarding claim 4, Lee teaches that wherein at least one chemotherapeutic agent includes a drug known to treat multiple myeloma in a subject (Page91, [000435]).
Regarding claim 5, Lee teaches that wherein at least one chemotherapeutic agent is selected from the group consisting of: a proteasome inhibitor (Page91, [000435]).
Regarding claim 6, Lee teaches that wherein the at least one chemotherapeutic agent is selected from the group consisting of: carfilzomib (Page91, [000435]).
Regarding claim 14, Lee teaches that wherein the labeling comprises contacting the incubated cells with at least one antibody selected from the group consisting of: anti-CD38 or anti-CD138 antibodies (Page 95, first paragraph, “CD138-PC5 and CD38-FITC antibodies”).
Regarding claim 16, Lee teaches that wherein the analyzing comprises gating the multiple myeloma cells on expression of one or more of CD38 and CD138 (Page 37, [000127]).
Regarding claim 18, Lee teaches that wherein the analyzing comprises determining that the multiple myeloma cells from the subject are sensitive to at least one chemotherapeutic agent when at least 20% cell death of the incubated multiple myeloma cells is detected (Pages 91-92, [000435], “In contrast, CD138+PMMCs cultured in fibrin were significantly more sensitive to melphalan”; 3/23, FIG.3, “(b)”, “80% viability of CD138 PMMC (corresponding to claimed at least 20% cell death) is observed in cells cultured in Fibrin (1% O2) and treated with 0.1-1 µM Melphalan”).
Regarding claim 19, Lee teaches that wherein the analyzing comprises determining that the multiple myeloma cells from the subject are resistant to at least one chemotherapeutic agent when less than 20% cell death of the incubated multiple myeloma cells is detected (Page 91, [000435], “When cultured with OSBs at both 1 and 20 % O2, CD138+PMMCs were highly resistant to 100 µM melphalan”; 3/23, FIG. 3, “(b)”, “80% viability of CD138 PM MMC (corresponding to claimed less than 20% cell death) is observed in cells cultured with OSB (20 % O2) and treated with up to 100 µM Melphalan”).
Regarding claim 20, Lee teaches that wherein the multiple myeloma cells are obtained from a subject at the time of initial diagnosis with multiple myeloma (Page 91, [000435], “(2) melphalan, which is often used to treat newly diagnosed MM patients”).
Regarding claim 23, Lee teaches treating multiple myeloma in the subject with at least one chemotherapeutic agent to which the subject's MM cells are identified to be sensitive to that agent, compared to the untreated control condition (Page 126, (e), “initiating therapy to treat the subject with the test therapeutic agent”).
Regarding claim 1, Lee does not teach that wherein incubating continues for a period of 48 hours after adding the therapeutic agent.
Lee does not teach incubating the multiple myeloma cells in a serum-free media comprising low density-lipoproteins.
Regarding claim 13, Lee does not teach that wherein the incubation further comprises conditions to mimic human plasma nutrient concentrations of amino acids and lipids.
Regarding claim 1, Sabatini teaches incubating a mammalian cell line for 48 hours (Page 90, [00246]).
Sabatini showed how to incubate the cells for a period of 48 hours before running any assays on the incubated mammalian cells or contacting the cells with a test agent for at least 24 hours (Pages 5-6, [0021]; page 90, [00246]; page 107, claim 59).
Sabatini made a growth rate comparison of the multiple myeloma cell line KMS12BM with other cells (Page 7, [0026], FIG. 1E; page 56, [00139]; page 90, [00245]).
Sabatini teaches using KMS12BM as a multiple myeloma cell line (Page 7, [0026], “KMS12BM (multiple myeloma)”).
Furthermore, Sabatini teaches that the cells are being contacted with an agent for at least 24 hours (Page 107, claim 59).
Sabatini teaches to optimize the present media formulation according to the type of cells to incubate (Page 31, [0081-082]; page 57, [00143]). Sabatini noted the need to perform meticulous tailoring of growth factors to support the culture of different cell types when using serum-free media (Page 70, [00175]).
Regarding claim 13, Sabatini teaches that wherein the incubation of a human cancer cell line such as with multiple myeloma further comprises conditions to mimic human plasma nutrient concentrations of amino acids and lipids (Page 7, [0026], “KMS12BM (multiple myeloma)”; page13, [0040]; page 54, [00132]; page 59 and 60, [00149]).
Regarding claim 1, Kovář teaches culturing myeloma derived cells with serum-free medium (Page 278, second paragraph).
Regarding claim 1, Huang teaches using a serum-free medium with low-density lipoproteins for cells (Page 21, [0170]). Huang supplemented the serum-free medium with BIT serum substitute which is similar to what the instant application used for making the humanized media (Specification, page 22, last paragraph, “This humanized media contains (BIT 9500 serum Substitute, StemCell Technologies)”). BIT 9500 or BIT is a serum substitute that has been developed for use in applications where a serum-free culture medium of defined composition is required (StemCell Technologies, Catalog#09500). BIT contains pre-screened batches of bovine serum albumin (BSA) that have been selected to support the optimal growth of human hematopoietic progenitor cells in serum-free media formulations (StemCell Technologies, Catalog#09500).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the culture conditions of multiple myeloma cells of Sabatini with the sensitivity assessment method of multiple myeloma cells of Lee to find an effective treatment for a patient with multiple myeloma because Sabatini mimicked the human conditions for multiple myeloma cells by offering concentrations of amino acids and lipids that mimic human plasma nutrient concentrations (Page 7, [0026], “KMS12BM (multiple myeloma)”; page13, [0040]; page 54, [00132]; page 59 and 60, [00149]). Also, Sabatini showed how to contact mammalian cells with a test agent for at least 24 hours (Pages 5-6, [0021]; page 90, [00246]; page 107, claim 59) and thus a skilled artisan is motivated to incubate a multiple myeloma cell line for at least 24 hours to see the medication effect over the cell line because Kovář noted the ability of hybridoma cells that are derived from myeloma cells to be grown for up to three days in a serum-free medium (Page 292, first paragraph). A skilled artisan is motivated to combine the serum-free medium of Kovář with the methods of Sabatini and Lee because Kovář noted the advantages of using serum-free medium for animal cell lines and for myeloma derived cells including economical and technical reasons (Page 278, second paragraph). Specifically, Kovář noted the ability to culture myeloma cells on a large-scale and with a well-defined medium for antibody production for example (Page 278, second paragraph). Sabatini clearly noted that the optimization of cell culture is needed based on the cell type and thus a skilled artisan is motivated to optimize the culture time and culture media as noted by Sabatini (Page 70, [0175]) and confirmed by Kovář (Page 279, first paragraph). A skilled artisan is further motivated to combine the low-density lipoproteins additives of Huang with the methods of Kovář, Sabatini and Lee because Huang teaches how to use low-density lipoproteins in serum-free medium for culturing mononuclear cells from the peripheral blood of a cancer patient (Page 21, [0170]), and suggests applying his method to treat a subject with multiple myeloma (Page 7, [0039]; page 37, claim 14). Thus, an artisan is motivated to combine the above methods and inventions to study the response of multiple myeloma cells to therapeutic agents in a favorable environment and to identify an effective treatment. A PHOSITA would have had a reasonable expectation of success in combining the methods of Huang, Kovář, Sabatini and Lee based on the methods being in the field of studying mononuclear cells. Consequently, it would have been obvious for a PHOSITA to use the synthetic culture media and ingredients of Huang, Kovář and Sabatini in the method of Lee to monitor the response of multiple myeloma cells to therapeutic agents and thus to come up with an effective treatment for multiple myeloma.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2018/064440 A1), Sabatini et al. (WO 2018/089928 A1), Kovář et al. (Methods in Enzymology, Vol. 121, 277-292), Huang et al. (US 2012/0316137 A1) and StemCell Technologies (Catalog# 09500, 2017) as applied to claim 1 above, and further in view of Superti-Furga et al. (US 2017/0356911 A1).
Regarding claims 10 and 11, the teachings and suggestions of Lee, Sabatini, Kovář, Huang and StemCell Technologies are described previously.
Moreover, regarding claims 10 and 11, Lee teaches incubating mononuclear cells (Page 33, [000117]; page 91, [000434] “seeded on the ossified tissue structure and cultured for up to 5 weeks” and [000435]).
Regarding claim 10, Lee does not teach that wherein the incubating comprises incubating about 1 x 102 to 1 x 108 mononuclear cells from the subject.
Regarding claim 11, Lee does not teach that wherein the incubating comprises incubating about 1 x 104 to 2 x 105 mononuclear cells from the subject.
Regarding claims 10 and 11, Superti-Furga teaches incubating peripheral blood mononuclear cells (PBMC) in the range of 1000 to 300000 (Page 13, [0068]).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine screening culture plate of Superti-Furga with the methods of Huang, Kovář, Sabatini and Lee to find an effective treatment for a patient with multiple myeloma because Superti-Furga offered using a screening plate for culturing a monolayer of peripheral blood mononuclear cells or bone-marrow cells (Abstract) and suggested the number of mononuclear cells to use for culturing and incubating (Page 13, [0068]). Superti-Furga further suggests a method to use for studying cell-cell interactions in multiple myeloma (Page 2, Table 1, “Multiple myeloma” and [0013]). Thus, a skilled artisan is motivated to combine the above methods and inventions to study the response of multiple myeloma cells to therapeutic agents. A PHOSITA would have had a reasonable expectation of success in combining the methods of Huang, Kovář, Lee, Sabatini and Superti-Furga based on the method being in the field of studying mononuclear cells. Consequently, it would have been obvious for a PHOSITA to use the methods of Huang, Kovář, Lee and Superti-Furga in the method of Lee to monitor the response of multiple myeloma cells to therapeutic agents and thus to come up with an effective treatment for multiple myeloma.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2018/064440 A1), Sabatini et al. (WO 2018/089928 A1), Kovář et al. (Methods in Enzymology, Vol. 121, 277-292), Huang et al. (US 2012/0316137 A1) and StemCell Technologies (Catalog# 09500, 2017) as applied to claim 1 above, and further in view of Perfetto et al. (Current Protocols in Cytometry 9.34.1-9.34.14, July 2010).
Regarding claim 15, the teachings and suggestions of Lee, Sabatini, Kovář, Huang and StemCell Technologies are described previously.
Moreover, regarding claim 15, Lee teaches that wherein the analyzing comprises contacting the labeled multiple myeloma cells with a fluorescent dye such as Annexin V to check their viability (Page 78, [000356]; page 87, [000418]; page 91, [000435]; page 113, [000494]).
Regarding claim 15, Lee does not teach using a fluorescent dye that binds to free amines within the multiple myeloma cells and on the surface of the multiple myeloma cells resulting in less intense fluorescence from live multiple myeloma cells.
Regarding claim 15, Perfetto teaches using a fluorescent dye that can cross the plasma membrane binds to free amines within cells resulting in fluorescence staining of dead cells or less intense fluorescence from live cells (Abstract).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the fluorescent viability dye of Perfetto with the methods of Huang, Kovář, Sabatini and Lee to find an effective treatment for a patient with multiple myeloma because Perfetto offered using a fluorescent dye that binds to free amines within the cells to differentiate between live and dead cells (Abstract) and suggested using amine reactive viability dyes as a powerful substitute for more traditional viability dyes in various staining panels (Page 9.34.1, second paragraph). Perfetto further suggests that the free amine dye is capable of detecting rare events and avoid nonspecific binding (Page 9.34.1, second paragraph). A skilled artisan is motivated to combine the above methods and inventions to study the response of multiple myeloma cells to therapeutic agents. A PHOSITA would have had a reasonable expectation of success in combining the methods of Perfetto, Huang, Kovář, Sabatini and Lee based on the methods being in the field of studying mononuclear cells. Consequently, it would have been obvious for a PHOSITA to use the fluorescent viability dye of Perfetto and the culture method of Huang, Kovář and Sabatini in the method of Lee to monitor the response of multiple myeloma cells to therapeutic agents and thus to come up with an effective treatment for multiple myeloma.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2018/064440 A1), Sabatini et al. (WO 2018/089928 A1), Kovář et al. (Methods in Enzymology, Vol. 121, 277-292), Huang et al. (US 2012/0316137 A1) and StemCell Technologies (Catalog# 09500, 2017) as applied to claim 1 above, and further in view of Hundemer et al. (WO 2015/181303 A1).
Regarding claim 17, the teachings and suggestions of Lee, Sabatini, Kovář, Huang and StemCell Technologies are described previously.
Moreover, regarding claim 17, Lee teaches that wherein the analyzing comprises gating the multiple myeloma cells on CD19- CD45+/- CD38+ CD138+ (Page 23, first paragraph, “Although MM tumor cells also are CD38+CD138+, 90% are CD19-, 99% are CD45- or CD45 lo”; page 91, [000435]).
Regarding claim 17, Lee does not teach gating the multiple myeloma cells expressing clonal light chain restriction on CD19- CD45+/- CD38+ CD138+.
Regarding claim 17, Hundemer teaches how to detect clonal light chain restriction of plasma and B cells (Page 1, lines 8-11).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine flow cytometry detection method of Hundemer with the methods of Huang, Kovář, Sabatini and Lee to find an effective treatment for a patient with multiple myeloma because Hundemer offered a method on how detect clonal light chain restriction of plasma and B cells using flow cytometry (Abstract) and suggested using the method to know the clonality of cells in multiple myeloma for therapeutic purposes (Page 7, lines 1-3). Thus, a skilled artisan is motivated to combine the above methods and inventions to identify multiple myeloma cells and to study their response to therapeutic agents. A PHOSITA would have had a reasonable expectation of success in combining the methods of Hundemer, Huang, Kovář, Sabatini and Lee based on the methods being in the field of studying mononuclear cells. Consequently, it would have been obvious for a PHOSITA to use the gating method of Hundemer and the culture method of Huang, Kovář and Sabatini in the drug assessment method of Lee to better identify multiple myeloma cells for monitoring their response to therapeutic agents and thus to come up with an effective treatment for multiple myeloma.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 2018/064440 A1), Sabatini et al. (WO 2018/089928 A1), Kovář et al. (Methods in Enzymology, Vol. 121, 277-292), Huang et al. (US 2012/0316137 A1) and StemCell Technologies (Catalog# 09500, 2017) as applied to claim 1 above, and further in view of Qiu et al. (CN105603087 A).
Regarding claims 21-22, the teachings and suggestions of Lee, Sabatini, Kovář, Huang and StemCell Technologies are described previously.
Regarding claims 21-22, Lee teaches that wherein the multiple myeloma cells are obtained from a subject at the time of a relapse of multiple myeloma (Page 77, [000352]).
Regarding claims 21-22, Lee does not teach the timing of the relapse.
Regarding claim 21, Qiu teaches that wherein the multiple myeloma cells are obtained from a subject at the time of first relapse of multiple myeloma and detected with mFISH ([0071] and [0164]).
Regarding claim 22, Qiu teaches that wherein the multiple myeloma cells are obtained from a subject at the time of second or subsequent relapse of multiple myeloma and detected with mFISH ([0071], [0163] and [0164]).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the method of studying clonal evolution conditions of Qiu with the methods of Huang, Kovář, Sabatini and Lee to find an effective treatment for a patient with multiple myeloma because Qiu offered a method to study the timing and order of relapse of multiple myeloma in patients ([0071], [0163] and [0164]) and taught how to study the clonal evolution conditions of multiple myeloma cells to guide the individualized therapy of patients ([0014]). Lee suggested that the order/ sequencing of the different effective treatment options is crucial to the outcome of multiple myeloma patients because multiple myeloma is a disease characterized by multiple relapses (Page26, [0102]). Thus, a skilled artisan is motivated to combine the above methods and inventions to study the response of multiple myeloma cells to therapeutic agents. A PHOSITA would have had a reasonable expectation of success in combining the methods of Qiu, Huang, Kovář, Sabatini and Lee based on the methods being in the field of studying mononuclear cells. Consequently, it would have been obvious for a PHOSITA to use Qiu’s method of studying multiple relapses of multiple myeloma with the culture method of Huang, Kovář and Sabatini in the assessment method of Lee to monitor the response of multiple myeloma cells to therapeutic agents and thus to come up with an effective treatment for multiple myeloma.
Response to Arguments
Applicant's arguments filed 08/25/2025 have been fully considered but they are not persuasive.
The Applicant argues that none of the references teach serum-free media nor incubating Bone marrow mononuclear cells (BMMC) for 48 hours. The Applicant alleges that there is no description or teaching in any of the references to suggest or teach incubating BMMC for 48 hours after contacting the cells with a therapeutic agent. The Applicant further alleged that Reference Sabatini teaches incubating HEK293 cells at 48 hours is different from incubating BMMC for 48 hours with a therapeutic agent as in the instant application. The applicant further alleged that HEK293 cells are different from multiple myeloma cells.
This argument is not found persuasive because both HEK293 cells and multiple myeloma cells are mammalian cells. Sabatini further notes incubating mammalian cells with an agent for at least 24 hours. A skilled artisan understands that the phrase “at least 24 hours” includes incubating at 48 hours with an agent based on the optimal culture conditions for each cell type. Last it is expected to optimize the conditions at which multiple myeloma cells grow the best and for what time any response is noted by the cells.
The instant case is a clear example of routine optimization within the prior art conditions or through routine experimentation. In order to properly support a rejection on the basis that an invention is the result of "routine optimization", the examiner must make findings of relevant facts, and present the underpinning reasoning in sufficient detail. The articulated rationale must include an explanation of why it would have been routine optimization to arrive at the claimed invention and why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range. See In re Stepan, 868 F.3d 1342, 1346, 123 USPQ2d 1838, 1841 (Fed. Cir. 2017). See also In re Van Os, 844 F.3d 1359,1361,121 USPQ2d 1209, 1211 (Fed. Cir. 2017) ("Absent some articulated rationale, a finding that a combination of prior art would have been ‘common sense’ or ‘intuitive’ is no different than merely stating the combination ‘would have been obvious.’"); Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355, 1362, 119 USPQ2d 1822 (Fed. Cir. 2016) ("[R]eferences to ‘common sense’ … cannot be used as a wholesale substitute for reasoned analysis and evidentiary support … ."). In the instant case, Sabatini clearly noted that the optimization of cell culture is needed based on the cell type and thus a skilled artisan is motivated to optimize the culture time and culture media as noted by Sabatini (Page 70, [0175]) and confirmed by Kovář (Page 279, first paragraph).
The Supreme Court has clarified that an "obvious to try" line of reasoning may properly support an obviousness rejection. In KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421, 82 USPQ2d at 1397 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the instant case, a skilled artisan is motivated to combine the culture conditions of multiple myeloma cells of Sabatini with the sensitivity assessment method of multiple myeloma cells of Lee to find an effective treatment for a patient with multiple myeloma because Sabatini mimicked the human conditions for multiple myeloma cells by offering concentrations of amino acids and lipids that mimic human plasma nutrient concentrations (Page 7, [0026], “KMS12BM (multiple myeloma)”; page13, [0040]; page 54, [00132]; page 59 and 60, [00149]). Also, Sabatini showed how to contact mammalian cells with a test agent for at least 24 hours (Pages 5-6, [0021]; page 90, [00246]; page 107, claim 59) and thus a skilled artisan is motivated to incubate a multiple myeloma cell line for at least 24 hours to see the medication effect over the cell line because Kovář noted the ability of hybridoma cells that are derived from myeloma cells to be grown for up to three days in a serum-free medium (Page 292, first paragraph). A skilled artisan is further motivated to combine the serum-free medium of Kovář with the methods of Sabatini and Lee because Kovář noted the advantages of using serum-free medium for animal cell lines and for myeloma derived cells including economical and technical reasons (Page 278, second paragraph).
The Applicant alleged that none of the references teaches the instant invention. However, the Applicant is reminded to look at the teachings of references in combination as it has been noted in the MPEP. Regarding the rejection of claims under 35 U.S.C. 103 and in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the references of Huang, Kovář, Sabatini and Lee teach culture techniques for mononuclear cells and multiple myeloma cells and with an incentive to combine and optimize as noted above the instant invention is reached.
The Applicant alleges that the discovery and disclosure of the improvement imparted by the preferred 48-hour incubation period on the multiple myeloma anti-cancer compound sensitivity testing assay is only found in the instant application. However, Kovář discusses incubating multiple myeloma derived cells in serum-free medium for up to three days and notes the advantages of using such media (Page 278, second paragraph).
The Applicant alleged that Sabatini does not teach the use of any serum-free media, and the Applicant further alleged that Sabatini rather teaches and demonstrates a human plasma-like medium that contains serum in every embodiment disclosed in Sabatini. However, Sabatini offered the use of culture media that comprise serum or a serum substitute (Page 4, [0014]) and clearly stated that other sources of supportive substances may be used instead of or in addition of serum (Page 26, [0074]). Sabatini gave examples for replacing serum in the cell culture media such as KnockOut™ Serum Replacement medium that is a free of fetal bovine serum or BIT9500 (StemCell Technologies) as used in the specification of the instant application (Specification of instant application, page 26, [0074]). Last the references that Sabatini gave for optimizing cell culture media are for serum-free animal culture media and this is consistent with Sabatini’s teaching of using serum-free media as an option (Page 31, [0081]). A skilled artisan is motivated to incubate a multiple myeloma cell line in a serum-free medium for at least 24 hours to see the medication effect over the cell line because Kovář noted the ability of hybridoma cells that are derived from myeloma cells to be grown for up to three days in a serum-free medium (Page 292, first paragraph).
The Applicant alleged that Sabatini specifically teaches the use of human plasma like media that contains serum (IFS or "heat inactivated fetal bovine serum" see Sabatini at [00174]). The Applicant alleged that Sabatini directly teaches away from the use of a serum-free media in such assays including those of the currently pending claims. However, as stated above, Sabatini is giving options on how to proceed with culturing different types of cells and not limiting their invention to one cell type or method (Abstract; page 44, [00113]).
The Applicant alleged that Huang teaches culturing peripheral blood mononuclear cells (PBMCs) for 12-24 hours (i.e., “overnight”) in serum-free media supplemented with a serum substitute and human low-density proteins. The Applicant further alleged that there is no motivation or reasonable expectation of success for one of skill in the art to substitute the growth media of Huang for the growth media of Lee to assess the sensitivity of multiple myeloma cells.
Regarding claim 1, Huang teaches using a serum-free medium with low-density lipoproteins for peripheral blood mononuclear cells (Page 21, [0170]). Huang supplemented the serum-free medium with BIT serum substitute which is similar to what the instant application used for making the humanized media (Specification, page 22, last paragraph, “This humanized media contains (BIT 9500 serum Substitute, StemCell Technologies)”). BIT 9500 or BIT is a serum substitute that has been developed for use in applications where a serum-free culture medium of defined composition is required (StemCell Technologies, Catalog#09500). BIT contains pre-screened batches of bovine serum albumin (BSA) that have been selected to support the optimal growth of human hematopoietic progenitor cells in serum-free media formulations (StemCell Technologies, Catalog#09500). A skilled artisan knows that there is a common origin between peripheral blood mononuclear cells and multiple myeloma cells. Thus, the skilled artisan is motivated to use similar media to grow a multiple myeloma cell line in a serum-free medium to eliminate the variability and potential contaminants that are found in animal-derived serum.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, Sabatini clearly noted that the optimization of cell culture is needed based on the cell type and thus a skilled artisan is motivated to optimize the culture time and culture media as noted by Sabatini (Page 70, [0175]) and confirmed by Kovář (Page 279, first paragraph).
Thus, the previous rejection of claims 1, 4-6, 10-11 and 13-23 under 35 U.S.C. 103, regarding obviousness, is maintained and is made final.
Conclusion
No claims are allowed.
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.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678