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 .
Claims 1-25 are under examination.
Claim Objections
Claim 24 is objected to because of the following informalities: In claim 24, the abbreviation “TEER” is not defined in the claim language. Appropriate correction is required.
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 23-24 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 23 recites the limitation "the difference in permeability" in line 2. There is insufficient antecedent basis for this limitation in the claim. The independent claim from which claim 23 depends from does not mention “a difference in permeability.” Claim 24 recites the limitation “the TEER value” in line 2. There is insufficient antecedent basis for this limitation in the claim. The independent claim from which claim 24 depends from does not mention “a TEER value.”
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.
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 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber (US 20190032021) in view of Braslavsky (WO 2018104935)
Ingber teaches a step of preparing an organ-on-a-chip comprising an organ-on-a-chip tissue part comprising a second channel that comprises cells and hydrogel and has a microchannel structure, and an organ-on-a-chip barrier part comprising a first channel that comprises cells and has a microchannel structure (Paragraphs 60,90-91, 94, 99-104, and Figures 2A and 2B) as in instant Claims 1 and 22.
Ingber does not teach the following: a step of perfusing a preservation solution containing a cryoprotectant through the microchannel included in the organ-on-a-chip barrier part; a step of refrigerated storage of the organ-on-a-chip; and
a step of cooling and freezing the organ-on-a-chip, a step of thawing the organ on a chip. However, Braslavsky teaches that biological samples on a chip (Page 4 of Braslavsky) can be successfully cryopreserved by first undergoing a refrigeration process after perfusing the sample with a cryoprotectant; the refrigeration step is then followed by a freezing step (Abstract, Pages 1-4 of Braslavsky). Braslavsky teaches that the frozen biological samples can be subsequently retrieved by thawing (Abstract and Page 1 of Braslavsky). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have cryopreserved and thawed the organ on the chip of Ingber using the method taught by Braslavsky. An artisan would have been motivated to have applied the refrigeration, cryopreservation, and thawing methods of Braslavsky because such methods are able to successfully preserve the cryopreserved cells over long stretches of time (Page 1 of Braslavsky) and keep the cells viable (Pages 28-29, Example 2 of Braslavsky). There would have been a high expectation for success because these processes taught by Braslavsky successfully preserve the cells and even promote cell viability after freezing/thawing (Example 2) as in instant Claims 1 and 22.
Dependent Claims taught by Ingber
Ingber teaches that the organ-on-a-chip part further comprises a side channel that is located on the side of the second channel and has a microchannel structure (212a and 212b of Figures 2A and 2B of Ingber) as in instant Claim 11. Ingber teaches wherein the tissue barrier cells include epithelial cells of the bronchi (Paragraphs 101-102 of Ingber) as in instant Claims 12-13. Ingber teaches that a membrane/scaffolding is positioned between the first channel/microchannel (Figures 2A and 2B, #208) and the second channel/microchannel (Figures 2A and 2B, #210) and a membrane/scaffolding separates these two channels (Figures 2A and 2B, #204) as in instant Claims 14-15. Ingber teaches the scaffold has a structure of a porous membrane (Paragraph 100 of Ingber) as in instant Claim 16. Ingber teaches wherein the hydrogel includes collagen gel, fibrin gel, or a combination (Paragraph 60 of Ingber) as in instant Claim 17. The second channel comprises internal tissue cells such as endothelial cells/internal tissue cells (Paragraph 101 of Ingber) as in instant Claims 20-21.
Dependent Claims taught by Braslavsky
Braslavsky teaches that the cryoprotectant used can be DMSO or glycerol (Page 4 of Braslavsky) as in instant Claims 2-3. Braslavsky teaches that the concentration of DMSO used can be in the range of 5%-10% (Page 4 of Braslavsky) as in instant Claims 4-6. Braslavsky teaches that the organ-on-a-chip is stored refrigerated for 10 to 20 minutes (Page 2, 1st paragraph; Page 3, 2nd paragraph of Summary of the Invention; Page 4, 2nd paragraph; Page 5, 1st paragraph of Braslavsky) as in instant Claims 7-8.
MPEP § 2144.05 (II) states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Claim 9 recites that the organ-on-a-chip is stored refrigerated at 4°C for 15 minutes. A review of the specification fails to provide evidence that the temperature and refrigeration period recited in the claim 9 is critical. Applicants have not shown that the refrigeration temperature of 4°C and the time period for refrigeration are critical for the refrigeration process. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing Braslavsky to try a finite number of refrigeration temperatures and different refrigeration time periods to predictably arrive at the claimed refrigeration temperature and length of time for refrigeration through routine optimization. An artisan would have had a reasonable expectation of success in optimizing the temperature and refrigeration time period because determining the temperature and duration of refrigeration were long established in the art as demonstrated by Braslavsky. Thus, Braslavsky renders the instant claimed temperature and refrigeration period recited in claim 9.
Braslavsky teaches that the cryopreservation medium can contain FBS (Example 1) as in instant Claim 10. Braslavsky teaches the same types of hydrogel material, the same cryoprotectant, and the same concentration of cryoprotectant, therefore, one would expect the organ on a chip exposed to these conditions to also have the same properties such as a difference in permeability rate of the organ-on-a-chip before and after freezing and thawing is 20% or less and a TEER value of the organ-on-a-chip before and after freezing and thawing is maintained at 80% or more as in instant Claims18, 23-24. Braslavsky teaches the same hydrogel, the same refrigeration process, the same cryopreservation process, and the same thawing process as taught by applicants. Thus, it would be expected that the hydrogel used would have the same expansion and contraction properties as recited in applicants claims. Therefore, it would be obvious for the hydrogel in Braslavsky to not exceed 10% in the expansion and contraction of the hydrogel before and after freezing as in instant Claim 19. Braslavsky teaches in Example 2 that the cells can be frozen slowly. A slower rate of freezing improves and allows for cell viability (Example 2 of Baslavsky). Braslavsky teaches that such viable cells in such a microfluidic chip share cell-cell junctions, such as gap junctions (Page 11 of Braslavsky). The viable cells remaining after cryopreservation and thawing (Example 2 of Braslavsky) are capable of producing and expressing receptor proteins as in instant Claim 25.
Ingber teaches a microfluidic chip that has a co-culture of different cells. Ingber does not teach that such a microfluidic chip can be cryopreserved as recited in the claims. However, Braslavsky teaches that such a microfluidic chip can be cryopreserved using the cryopreservation teachings of Braslavsky. An artisan would have been motivated to have used such a cryopreservation method because it successfully preserves the viability of cells. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicant’s invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All of the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSA International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007)). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.'s and Ph.D.'s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cell culture, microfluidics, and nanotechnology. Therefore, the level of ordinary skill in this art is high.
Claims 1-10,12-25 are rejected under 35 U.S.C. 103 as being unpatentable over Kearns (US 20180185844) in view of Braslavsky (WO 2018104935)
Kearns teaches a step of preparing an organ-on-a-chip comprising an organ-on-a-chip tissue part comprising a second channel that comprises cells and hydrogel and has a microchannel structure (Paragraph 169-174 and 184), and an organ-on-a-chip barrier part comprising a first channel that comprises cells and has a microchannel structure (Paragraph 184); as in instant Claims 1 and 22.
Kearns does not teach the following: a step of perfusing a preservation solution containing a cryoprotectant through the microchannel included in the organ-on-a-chip barrier part; a step of refrigerated storage of the organ-on-a-chip; and
a step of cooling and freezing the organ-on-a-chip, a step of thawing the organ on a chip. However, Braslavsky teaches that biological samples on a chip can be successfully cryopreserved by first undergoing a refrigeration process after perfusing a cryoprotectant; the refrigeration step is then followed by a freezing step (Abstract, Pages 1-4 of Braslavsky). Braslavsky teaches that the frozen biological sample can be subsequently retrieved by thawing (Abstract and Page 1 of Braslavsky). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have refrigerated, cryopreserved, and thawed the chip taught in Kearn using the teaching of Braslavsky. An artisan would have been motivated to have the applied the refrigeration/cryopreservation method of Braslavsky because such methods are able to successfully preserve the cryopreserved cells over long stretches of time (Page 1 of Braslavsky) and the thawing process taught by Braslavsky allows for such biological material to be effectively harvested (Abstract of Braslavsky) as in instant Claims 1 and 22.
Dependent Claims taught by Kearns
Kearns teaches that the first channel comprises tissue barrier cells (Paragraphs 140 and 143 of Kearns) as in instant Claim 12. Kearns teaches that the tissue barrier cells include vascular endothelial cells; skin cells; cancer cells, small intestine, pancreas, or kidney (Paragraphs 140 and 143) as in instant Claim 13. Kearns teaches that the organ-on-a-chip further comprises a scaffold between the first channel and the second channel (Paragraph 130 of Kearns) as in instant Claim 14. Kearns teaches that the scaffold and the second channel are in contact with each other (Paragraph 130 of Kearns) as in instant Claim 15. Kearns teaches that the scaffold has a structure of a porous membrane (the collagen gel mentioned in Paragraph 130 would be considered porous) as in instant Claim 16. Kearns teaches that the hydrogel includes one or more selected from the group consisting of collagen gel, peptide gel (Paragraph 209 of Kearns) as in instant Claim 17. Kearns taches that keratinocytes/internal tissue cells can be present (Paragraph 27) as in instant Claims 20-21.
Dependent Claims taught by Braslavsky
Braslavsky teaches that the cryoprotectant used can be DMSO or glycerol (Page 4 of Braslavsky) as in instant Claims 2-3. Braslavsky teaches that the concentration of DMSO used can be in the range of 5%-10% (Page 4 of Braslavsky) as in instant Claims 4-6. Braslavsky teaches that the organ-on-a-chip is stored refrigerated for 10 to 20 minutes (Page 2, 1st paragraph; Page 3, 2nd paragraph of Summary of the Invention; Page 4, 2nd paragraph; Page 5, 1st paragraph of Braslavsky) as in instant Claims 7-8.
MPEP § 2144.05 (II) states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Claim 9 recites that the organ-on-a-chip is stored refrigerated at 4°C for 15 minutes. A review of the specification fails to provide evidence that the temperature and refrigeration period is critical. Applicants have not shown that the refrigeration temperature of 4°C and the time period of 15 minutes are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing Braslavsky to try a finite number of refrigeration temperatures at different refrigeration periods/lengths of time to predictably arrive at the claimed refrigeration temperature and refrigeration duration through routine optimization. An artisan would have had a reasonable expectation of success in optimizing the temperature and refrigeration duration because determining the temperature and duration of refrigeration were long established in the art as demonstrated by Braslavsky. Thus, Braslavsky renders the instant claimed temperature and refrigeration period recited in claim 9.
Braslavsky teaches that the cryopreservation medium can contain FBS (Example 1) as in instant Claim 10. Braslavsky teaches the same types of hydrogel material, the same cryoprotectant, and the same concentration of cryoprotectant, therefore, one would expect that the organ on a chip exposed to these conditions to also have the same properties such as a difference in permeability rate of the organ-on-a-chip before and after freezing and thawing of 20% or less and a TEER value of the organ-on-a-chip before and after freezing and thawing is maintained at 80% or more as in instant Claims18, 23-24. Braslavsky teaches the same hydrogel as taught by applicant, the same refrigeration, cryopreservation, and thawing processes as taught by applicants. Thus, it would be expected that the hydrogel used would have the same expansion and contraction properties as recited in applicants claims. Therefore, expansion and contraction of the hydrogel before and after freezing not exceeding 10% would have been obvious as in instant Claim 19.Braslavsky teaches in Example 2 that the cells can be frozen slowly. A slower rate of freezing improves cell viability (Example 2 of Baslavsky). Because Braslavsky teaches that the cells are preserved and viable. Baslavsky teaches that such viable cells in such a microfluidic chip share cell-cell junctions, such as gap junctions (Page 11 of Baslavsky). The viable cells remaining after cryopreservation and thawing (Example 2 of Baslavsky) are inherently capable of producing and expressing receptor proteins as in instant Claim 25.
Kearns teaches a microfluidic chip that has a co-culture of different cells. Kearns does not teach that such a microfluidic chip can be cryopreserved. However, Braslavsky teaches that such a microfluidic chip can be cryopreserved using the cryopreservation teachings of Braslavsky. An artisan would have been motivated to have used such a cryopreservation method because it successfully preserves the viability of cells. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicant’s invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All of the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSA International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007)). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.'s and Ph.D.'s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, and inflammatory therapy. Therefore, the level of ordinary skill in this art is high.
Conclusion
All clams stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638