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 .
Status of the Claims
Claims 1-15 and 17-19 are currently pending.
Claim 16 is cancelled.
New claims 17-19 have been added.
Claims 1-15 and 17-19 have been considered on the merits.
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 1-15 and 17-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 contains the phrase “adding a… aqueous solution into an HL-1 mouse cardiomyocyte for passage” in lines 3-4, which is indefinite. It is unclear whether or not the aqueous solutions listed at lines 3-4 are meant to be injected into cells or if they are meant to be added to an HL-1 cardiomyocyte culture. Appropriate correction is required.
Claim 2 contains the phrase “adding 0.25% trypsin in PBS, so that the 0.25% trypsin in PBS is covered over the HL-1 mouse cardiomyocytes” in lines 6-7, which is indefinite. The recitation of the phrase “so that” renders this phrase unclear because it is unclear if the limitations recited after the phrase are required limitations. Appropriate clarification is required.
Claims 13 recites that the “Zn(NO3)2·6H2O aqueous solution and the culture medium in step 8 have a volume ratio of 6.25 x 10-5 to 1.67 x 10-3”, which is indefinite. It is not clear if the volume ratio is meant to be read as a 6.25 x 10-5: 1 to 1.67 x 10-3 :1 (Zn solution: culture media) or 6.25 x 10-5 : 1.67 x 10-3 (Zn solution: culture media). Additionally, volumes of Zn solution and culture media are not recited in the claims and therefore it is unclear if applicant is claiming any/all volumes of Zn solution present at a ratio defined by claim 13. Appropriate clarification is required. For the sake of compact prosecution, the limitations of claim 13 are interpreted to be met by any ratio of Zn solution to culture media recited in the art.
Claims 14 recites that the “2-methylimidazole aqueous solution and the culture medium in step 8 have a volume ratio of 6.25 x 10-5 to 1.67 x 10-3”, which is indefinite. It is not clear if the volume ratio is meant to be read as a 6.25 x 10-5: 1 to 1.67 x 10-3 :1 (2-methylimidazole solution: culture media) or 6.25 x 10-5 : 1.67 x 10-3 (2-methylimidazole solution: culture media). Additionally, volumes of 2-methylimidazole solution and culture media are not recited in the claims and therefore it is unclear if applicant is claiming any/all volumes of 2-methylimidazole solution present at a ratio defined by claim 13. Appropriate clarification is required. For the sake of compact prosecution, the limitations of claim 13 are interpreted to be met by any ratio of 2-methylimidazole solution to culture media recited in the art.
Claim Rejections - 35 USC § 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al (WO2020068798A1), in view of Xu (Biofabrication, 2014), Wang (Adv. Healthc. Mater., 2018).
Regarding independent claim 1, Guo teaches a method of preparing a metal organic framework (MOF) coated cell (pg. 20, last para). Guo teaches that the cell can be a cardiac cell as required by claim 1 (pg. 3, para 2). Guo teaches a step of adding an aqueous solution of Zn(NO3)2·6H2O (referred to as “Zn solution” throughout the following rejections) and an aqueous solution of 2-methylimidazole (pg. 18, para 2) to a mammalian cell culture (pg. 20, para 3-4) and culturing the cells for at least 1 day thereby obtaining MOF-coated cells as required by claim 1 (pg. 23, para 4). Guo teaches that the cells are then washed/passaged twice and resuspended in culture media (pg. 20, para 3-4).
Guo does not explicitly teach that the cardiac cells are HL-1 mouse cardiomyocytes as required by claim 1.
However, Xu teaches the use of HL-1 mouse cardiomyocytes ( pg. 3, para 2). Xu teaches that the HL-1 cardiac muscle cell line is derived from AT-1 cardiomyocytes and the cells are able to continuously divide and spontaneously contracts while maintaining a differentiated state (pg. 3, para 2).
One of ordinary skill would find it obvious at the effective filling date of the instant invention to combine the method of MOF coating mammalian cells, including cardiac cells, taught by Guo with the HL-1 cardiomyocytes taught by Xu to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Guo teaches the method is able to be used on cardiac cells and Xu teaches that the HL-1 cardiac muscle cell line is derived from AT-1 cardiomyocytes and the cells are able to continuously divide and spontaneously contracts while maintaining a differentiated state (pg. 3, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Guo with Xu because Guo teaches the necessary steps to coat a cell with an MOF and Xu teaches the successful culture of HL-1 cells.
Guo and Xu do not teach that the concentration of the Zn solution is between 1-10 g/L and that the concentration of the 2-methylimidazole solution is between 5-20 g/L as required by claim 1.
However, Wang teaches a method of encapsulating insulin with Zn solution and 2-methylimidazole, termed ZIF-8 (abstract). Wang teaches that when using 20 mM Zn solution and 80 mM 2-methylimidazole solution the highest preservation efficacy was achieved (pg. 5, para 2). A 20 mM Zn solution equates to a 5.95 g/L concentration and a 80 mM 2-methylimidazole solution equates to a 6.57 g/L concentration as required by claim 1 (pg. 5, para 2). Additionally, Wang teaches that cell toxicity tests were conducted with high concentrations of dissociated ZIF-8 particles which showed low cytotoxicity (pg. 7, para 3). Wang also indicates that after the ZIF-8 coated insulin is administered to mice, abnormalities or lesions were not observed in the heart and other organs, indicating that the ZIF-8 MOF has excellent biocompatibility.
One of ordinary skill would find it obvious at the effective filling date of the instant invention to combine the method of MOF coating of HL-1 cells taught by Guo and Xu with the concentrations of Zn solution and 2-methylimidazole solution taught be Wang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Wang teaches that when using 20 mM Zn solution and 80 mM 2-methylimidazole solution the highest preservation efficacy was achieved (pg. 5, para 2) and Wang teaches that cell toxicity tests were conducted with high concentrations of dissociated ZIF-8 particles which showed low cytotoxicity (pg. 7, para 3). One of ordinary skill in the art would have a reasonable expectation of success when combining Guo and Xu with Wang because Wang also indicates that after the ZIF-8 coated insulin is administered to mice, abnormalities or lesions were not observed in the heart and other organs, indicating that the ZIF-8 MOF has excellent biocompatibility.
Additionally, the combination of Guo, Xu, and Wang would result in the product of a HL-1 cardiomyocyte with an MOF-coating as required by claim 15.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) 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.
With regards to claim 1 which recites a limitation of “the passage is conducted in a ratio of 1:(2-8)”, rationales A, B, D, and E are applicable. Passaging cells at a desired ratio is well known to a person or ordinary skill in the art. Additionally, passaging cells at a ratio of between 1:2 and 1:8 is both well-known and obvious to try. The teachings of Guo, Xu, and Wang provide detailed cell culture procedures, in which passaging the cells at a ratio between 1:2 and 1:8 would reasonably result in success. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
With regards to the combination of Guo and Xu with the specific concentrations of the Zn solution and 2-methylimidazole of Wang, rationales A and B are applicable. The method of MOF coating cells is taught by Guo and the combination with Wang is an example of a simple substitution of the known concentrations of Zn solution and 2-methylimidazole of Wang with the application of Guo to obtain predictable results. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 2-4, 6-9, and 12-14 is rejected under 35 U.S.C. 103 as being unpatentable over Guo et al (WO2020068798A1), in view of Xu (Biofabrication, 2014), Wang (Adv. Healthc. Mater., 2018), Millipore (“HL-1 Cardiac Muscle Cell Line”, Cat. # SCC065, 2017), and Deng et al (EU Jour Pharmacology, 2009).
Claim Interpretation: Claims 13 and 14 are rejected above for being indefinite regarding the recited volume ratios. For the sake of compact prosecution, the limitations of claim 13 are interpreted to be met by any ratio of 2-methylimidazole solution to culture media recited in the art because it is not clear how one would apply the ratio claimed. See 112(b) rejection above for more detail. Regarding independent claim 2, Guo teaches a method of preparing a metal organic framework (MOF) coated cell (pg. 20, last para). Guo teaches that the cell can be a cardiac cell as required by claim 2 (pg. 3, para 2). Guo teaches steps 1-3 of claim 2 through teaching that adherent cells were removed from the culture container using .25% trypsin as required by claim 2, 3, and 7 (pg. 20, para 3). Guo teaches that the cells are maintained at 37°C and 5% CO2 in all recitations of culture parameters as required by claims 2, 4, 5, and 13 (pg. 20, para 3). Guo teaches that that after the trypsin treatment the cells are resuspended in culture media as required by claim 3 (pg. 20, para 3). Guo teaches generally that cells are passaged at around 80% confluency (pg. 20, para 3). Guo teaches step 7 of preparing aqueous solutions of both the Zn(NO3)2·6H2O (referred to as “Zn solution” throughout the following rejections) and 2-methylimidazole solution as required by claim 2 (pg. 18, para 2). Guo teaches a step of adding Zn solution and an aqueous solution of 2-methylimidazole (pg. 18, para 2) to a mammalian cell culture as required by claims 13 and 14 (pg. 20, para 3-4) and culturing the cells for at least 1 day thereby obtaining MOF-coated cells as required by claim 2 (pg. 23, para 4). Guo teaches that the cells are then washed/passaged twice and resuspended in culture media (pg. 20, para 3-4).
Guo does not explicitly teach that the cardiac cells are HL-1 mouse cardiomyocytes as required by claim 2.
However, Xu teaches the use of HL-1 mouse cardiomyocytes ( pg. 3, para 2). Xu teaches that the HL-1 cardiac muscle cell line is derived from AT-1 cardiomyocytes and the cells are able to continuously divide and spontaneously contracts while maintaining a differentiated state (pg. 3, para 2). Xu also teaches that the cells are maintained at 37°C and 5% CO2 in DMEM supplemented with 10% FBS, and 1% antibiotic antimycotic (a penicillin/streptomycin double antibody) (pg. 3, para 2). Finally, Xu teaches that when confluency is reached the cells are removed using trypsin and collected by centrifugation at 1000 rpm for 5 minutes as required by claims 8 and 12 (pg. 3, para 2).
One of ordinary skill would find it obvious at the effective filling date of the instant invention to combine the method of MOF coating mammalian cells, including cardiac cells, taught by Guo with the HL-1 cardiomyocytes and specific culture parameters taught by Xu to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Guo teaches the method is able to be used on cardiac cells and Xu teaches that the HL-1 cardiac muscle cell line is derived from AT-1 cardiomyocytes and the cells are able to continuously divide and spontaneously contracts while maintaining a differentiated state (pg. 3, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Guo with Xu because Guo teaches the necessary steps to coat a cell with an MOF and Xu teaches the successful culture of HL-1 cells.
Guo and Xu do not teach that the concentration of the Zn solution is between 1-10 g/L and that the concentration of the 2-methylimidazole solution is between 5-20 g/L as required by claim 2.
However, Wang teaches a method of encapsulating insulin with Zn solution and 2-methylimidazole, termed ZIF-8 (abstract). Wang teaches that when using 20 mM Zn solution and 80 mM 2-methylimidazole solution the highest preservation efficacy was achieved (pg. 5, para 2). A 20 mM Zn solution equates to a 5.95 g/L concentration and a 80 mM 2-methylimidazole solution equates to a 6.57 g/L concentration as required by claim 1 (pg. 5, para 2). Additionally, Wang teaches that cell toxicity tests were conducted with high concentrations of dissociated ZIF-8 particles which showed low cytotoxicity (pg. 7, para 3). Wang also indicates that after the ZIF-8 coated insulin is administered to mice, abnormalities or lesions were not observed in the heart and other organs, indicating that the ZIF-8 MOF has excellent biocompatibility.
One of ordinary skill would find it obvious at the effective filling date of the instant invention to combine the method of MOF coating of HL-1 cells taught by Guo and Xu with the concentrations of Zn solution and 2-methylimidazole solution taught be Wang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Wang teaches that when using 20 mM Zn solution and 80 mM 2-methylimidazole solution the highest preservation efficacy was achieved (pg. 5, para 2) and Wang teaches that cell toxicity tests were conducted with high concentrations of dissociated ZIF-8 particles which showed low cytotoxicity (pg. 7, para 3). One of ordinary skill in the art would have a reasonable expectation of success when combining Guo and Xu with Wang because Wang also indicates that after the ZIF-8 coated insulin is administered to mice, abnormalities or lesions were not observed in the heart and other organs, indicating that the ZIF-8 MOF has excellent biocompatibility.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) 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.
Claim 2: Steps 1-6 and Claims 3, 6, and 7
Guo and the cited art do not explicitly teach each detail of steps 1-6 of claim 2, claim 3 which limits step 1 of claim 2, or claims 6 and 7 which limit step 3, however steps 1-6 provide a step wise explanation of completing a basic culture protocol of detaching cells from adherent culture. Both Guo and Xu teach methods including culturing and dissociating adherent cells and provide statements such as “For coating purposes, living adherent cells (HeLa and A549) were removed from plate bottom using Trypsin-20 EDTA (0.25%) and then suspended in culture media” (Guo, pg. 20, para 3) and “When reaching confluence, the cells were removed from the flasks by the aid of trypsin-EDTA (Sigma) and collected by centrifugation (1000 rpm, 5 min)” (Xu, pg. 3, para 2). These statements exemplify that a person of ordinary skill in the art does not require a detailed explanation as to how one might go about dissociating cells for adherent culture and preparing them by washing the cells of the remaining trypsin prior to using them for the desired purposes. Any person of ordinary skill in the art would be able to arrive at the instant steps 1-6 given the information provided by Guo and/or Xu (quoted above).
Millipore (“HL-1 Cardiac Muscle Cell Line”, Product information, 2017 (see bottom right hand side of document)) provides a product overview of the HL-1 cell line. Millipore teaches multiple protocols needed for the successful culture of HL-1 cells. Within two of these protocols, dissociation is described as “When the cells are 100% confluent, they can be dissociated with 0.05% Trypsin in 0.02% EDTA (Sigma T3924) and further passaged or, alternatively, frozen for later use” (pg. 1, col 2, step 20) and “Dissociate the confluent layer of HL-1 cells with 0.5% Trypsin in 0.02% EDTA (Sigma T3924)” (pg. 3, step 3). Therefore, even within the specific protocols provided by Millipore, it is expected that the person of ordinary skill in the art is able to successfully apply a trypsin solution to adherent cells and dissociate them prior to using the cells for the person of ordinary skill’s desired purpose.
Deng et al (EU Jour of Pharmacology, 2009) also provides methods and protocols involving the use of HL-1 cells. Regarding the step of employing trypsin to dissociate the HL-1 cells, Deng states “Single HL-1 cells were isolated from the culture dishes using a 2 min enzymatic dissociation with 0.05% trypsin-EDTA. Digestion was stopped by adding 0.025% trypsin inhibitor and medium” (pg. 2, col. 1, para 2). Deng provides that the trypsin be used for a specific length of time, 2 minutes, required by claim 7. However, Deng, like Millipore, also exemplifies that it is expected that the person of ordinary skill in the art is able to successfully apply a trypsin solution to adherent cells and dissociate them with a minimal direction provided.
Therefore, with regards to claim 2: steps 1-6 and claims 3 and 7, KSR rationales A, C, and E are applicable. Guo, Xu, and Millipore demonstrate that the steps 1-6 of claim 2 are merely combining prior art elements according to known methods to yield predictable results, use of known technique to improve similar devices (methods, or products) in the same way, and obvious to try. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Claim 2: Step 7
With regards to the combination of Guo and Xu with the specific concentrations of the Zn solution and 2-methylimidazole of Wang, rationales A and B are applicable. The method of MOF coating cells is taught by Guo and the combination with Wang is an example of a simple substitution of the known concentrations of Zn solution and 2-methylimidazole of Wang with the application of Guo to obtain predictable results. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 2, 5, 10, 11, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al (WO2020068798A1), in view of Xu (Biofabrication, 2014) and Wang (Adv. Healthc. Mater., 2018), Millipore (“HL-1 Cardiac Muscle Cell Line”, Cat. # SCC065, 2017), and Deng et al (EU Jour Pharmacology, 2009), as applied to claims 2-4, 6-9, and 12 above, and in further view of Kuznetsov et al (Biochem Biophys Acta, 2015).
Claim Interpretation: Claims 5, 10, 11, 17, and 18 recite the limitation of a “double antibody”, which is being interpreted to mean a “double antibiotic” due to the claimed concentration in the culture medium being 1% w/w and that each antibiotic would have a final concentration of 100 U/mL. These concentrations are consistent with double antibiotics typically employed in culture media.
Regarding claims 5, 10, 11, and 17-19, Guo, Xu, and Wang teach the limitations of the independent claim 2 above.
Xu teaches the use of HL-1 mouse cardiomyocytes (pg. 3, para 2). Xu teaches that the HL-1 cardiac muscle cell line is derived from AT-1 cardiomyocytes and the cells are able to continuously divide and spontaneously contracts while maintaining a differentiated state (pg. 3, para 2). Xu also teaches that the cells are maintained at 37°C and 5% CO2 in DMEM supplemented with 10% FBS, and 1% antibiotic antimycotic (Sigma, a penicillin/streptomycin double antibody with a final concentration of 100 u/mL) as required by claims 5, 10, 11, 17, and 18 (pg. 3, para 2). Finally, Xu teaches that when confluency is reached the cells are removed using trypsin and collected by centrifugation at 1000 rpm for 5 minutes as required by claims 8, 12 and 19 (pg. 3, para 2).
Xu and the other cited references do not teach that the DMEM is DMEM high glucose as required by claims 5, 10, 11, 17, and 18.
However, Kuznetsov teaches about HL-1 cells. Kuznetsov teaches that HL-1 cells have a high dependency on glucose (pg. 9, para 1). Additionally, Kuznetsov teaches that “Furthermore, the use of glucose as a major energy substrate by HL-1 cells is explained by the fact that they are cancerous cells. High levels of hexokinase were previously observed in HL-1 cells, indicating a glycolytic phenotype of energy metabolism, a common characteristic of cancer cells (Warburg effect)” (pg. 8, para 2). Based on the teachings of HL-1 cells having a high dependency on glucose by Kuznetsov, it would be obvious to use DMEM high glucose rather than the basic DMEM as required by claims 5, 10, 11, 17, and 18.
One of ordinary skill would find it obvious at the effective filling date of the instant invention to combine the method of MOF coating of HL-1 cells taught by Guo, Xu, and Wang using DMEM taught by Xu with a high glucose concentration taught to be necessary for HL-1 cells by Kuznetsov to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Kuznetsov teaches that “Furthermore, the use of glucose as a major energy substrate by HL-1 cells is explained by the fact that they are cancerous cells. High levels of hexokinase were previously observed in HL-1 cells, indicating a glycolytic phenotype of energy metabolism, a common characteristic of cancer cells (Warburg effect)” (pg. 8, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining the cited art with Kuznetsov because Xu teaches the culture of HL-1 cells and Kuznetsov teaches that HL-1 cells have higher glucose needs due to being a cancerous cell line.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) 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.
With regards to the limitation requiring 9% FBS in the culture media defined in claims 5, 10, 11, 17, and 18, rationales A, B, and E are applicable. Although the cited art teaches a culture medium including 10% FBS, a person of ordinary skill in the art would understand that including 9% FBS, a variation of only 1%, would be obvious to try with a reasonable expectation of success. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/DAVID A MONTANARI/Examiner, Art Unit 1632