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
This application was filed Jan. 27, 2022, and claims benefit to the 371 application of PCT/CN2019/099246 filed on August 5, 2019.
Status of Claims
On March 13, 2025, Applicant elected Group II, Claims 25-28 and 32-38, and the species of Method B and Cell culture vessel II, with traverse.
In the response filed Oct. 14, 2025, Applicants have amended claims 25-28, and 32-35, and canceled claims 29-31 and 39-40. Further, Applicants have amended claims 32-35 to the elected species (i.e. the species of Method B and Cell culture vessel II) and are dependent on claim 25. Therefore, claims 32-34 have been rejoined.
Claims 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (i.e. Group I and method A), there being no allowable generic or linking claim.
Currently, claims 25-28 and 32-38 are under consideration.
Response to Traversal:
Applicant argues that there are a number of fundamental distinction between the medium defined by the pending claims and the prior art of Li Hui (CN107151645). Applicant maintains the position that Hui does not anticipate or obviate the pending claims (Remarks, page 14-15).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument, the examiner was able to provide art (Li Hui, CN107151645), which satisfied the limitation of the cultivation method of lung tumor epithelial cell in lung cancer patient of Group II, thereby demonstrating that the special technical feature lacks novelty. Even though Applicant’s response has amended the claims (e.g. narrowed the scope) and amend the claims to adopt the “consisting of” language, as stated in the non-final on July 11, 2025, the prior art of Liu et al., (WO2018094410A1, published 2018, prior art of record), Sachs et al., (US2017/0275592A1, published 2017, prior art of record), Herreño, et al. (Cogent Medicine 5.1: 1503071, published 2018, hereinafter as “Herreno”, prior art of record), Willett et al. (American journal of respiratory cell and molecular biology 18.4: 489-496, published 1998, prior art of record), Yoshimura et al. "(Journal of Biological Chemistry 268.21: 15461-15468, published 1993, prior art of record), Inoue et al., (WO2011068183A1, published 2011, prior art of record), Timmins, et al., (WO2017127921A1, published 2017, prior art of record), and Bray et al., (Science 214.4522: 793-795, published 1981, prior art of record), make obvious the technical features that are shared between the Groups. Thus, a feature found in the prior art cannot be considered a special technical feature. Therefore, a lack of unity exists between the restricted groups (PCT Lack of Unity practice). It is noted that the expression “special technical feature” refers to those feature that define a contribution which each of the claimed invention, considered as a whole makes over the prior art.
It is noted that in the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
However, the requirement is still deemed proper and is therefore made FINAL.
Currently, claims 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (i.e. Group I and method A), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 13, 2025.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
The Claims are objected to because of the following informalities:
Claim 25 is objected to for reciting “(b1) and (b2)” and since there is no recitation of the “method B,” it is suggested that claim 25 recite (1) and (2).
Claim 26 is objected to for reciting the acronym PBS without first spelling out “Phosphate-Buffered Saline”.
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 25-28, and 32-38 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.
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on July 11, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claims 25, 27-28, 33, and 35 recite trademarks/trade names (i.e. GlutaMax, CYTOP, B27, ITS-X, Advanced DMEM/F12 medium, Accutase, and TrypLE). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademarks/trade (i.e. “GlutaMax”, “CYTOP”, and “TrypLE”) are used to identify/describe compositions comprised within a cell culture medium; accordingly, the identification/description is indefinite. Thus, claims 26, 29-32, and 34-40 are included in this rejection due to their dependence from rejected claim 25 or 27. Appropriate correction is required.
Response to Traversal:
Applicant argues that the claim has been amended to include the trademarks/trade name symbol for “GlutaMax”, “CYTOP”, and “TrypLE,” and the 112b rejection should be withdrawn.
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
It is acknowledged that Applicant has amended the claims to include the trademarks/trade name symbol for “GlutaMax”, “CYTOP”, and “TrypLE.” However, the addition of the trademarks symbol does not equate to the underlying composition (i.e. claim limitations) that the trademark name encompasses (e.g. trademark symbols can change). Therefore, it is unclear to a person of ordinary skill in the art because the claim does not recite all the limitation needed to identify or describe a particular material or product.
Claims 32-34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
This rejection is a new rejection necessitated by amendments to the claims.
Claim 33-34, dependent on claim 32, recites the limitation "cell digestion solution” and “cell digestion termination solution” for the passage. There is a lack of insufficient antecedent basis for this limitation in the claim and renders the claim indefinite because there is no prior recitation of any "cell digestion solution” and “cell digestion termination solution” for cell passaging that could be interpreted as the “cell digestion solution” and “cell digestion termination solution”. As such the recitation is indefinite because it is not apparent to what "cell digestion solution” and “cell digestion termination solution” for the passaging that it is referring, given the base claims does not require one. Thus, there is insufficient antecedent basis for this limitation in the claim.
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 25-26, 32, and 35-38 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al., (WO2018094410A1, published 2018, prior art of record), Sachs et al., (US2017/0275592A1, published 2017, prior art of record), Herreño, et al. (Cogent Medicine 5.1: 1503071, published 2018, hereinafter as “Herreno”, prior art of record), Willett et al. (American journal of respiratory cell and molecular biology 18.4: 489-496, published 1998, prior art of record), Yoshimura et al. "(Journal of Biological Chemistry 268.21: 15461-15468, published 1993, prior art of record), Inoue et al., (WO2011068183A1, published 2011, prior art of record), Timmins, et al., (WO2017127921A1, published 2017, prior art of record), and Bray et al., (Science 214.4522: 793-795, published 1981, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on July 11, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claims 25 and 36-38, Liu discloses a method for culturing primary cells from cancer, such as lung cancer and non-small-cell lung cancer squamous cell carcinoma. (i.e. human epithelial tumor cells)(See e.g. abstract, page 22). Further, Liu discloses a method for culturing primary cells from solid tumor tissues of lung cancer (i.e. primary epithelial tumor cells), and wherein the primary cells of lung cancer are primary cells from solid tumor of lung cancer or primary tumor cells from pleural effusion of lung cancer (See e.g. abstract, page 2, 10, 22, 28 and claim 1-2 and 20).
Regarding claim 25, step (b1), Liu discloses separating primary tumor cells from pleural effusion of lung cancer to obtain primary tumor cells from pleural effusion of lung cancer (see e.g. page 12 and 28 and claim 1, 9).
Regarding claim 25, step (b2), Liu discloses suspension-culturing the dissociated primary cells from solid tumor of lung cancer in step (b1) with a medium (see e.g. page 28, claim 1, 9).
Regarding claim 25, medium, Liu discloses a growth medium with defined medium such as Dulbecco's Modified Eagles Medium (DMEM), Ham's Nutrient Mixture (F12) (DMEM/F12) that utilizes a ROCK inhibitor Y-27632 in a final concentration range of 5-20 μM (see e.g. pages 3, 4, 7, 15, 18, 19, 25, Example 1, figs. 3-5, 8). Further, Liu discloses that the DMEM/F12, which is supplemented with additional components, for example, growth factors, antioxidants, and/or energy sources (see e.g. page 15).
Liu does not explicitly state a medium that consists of a dual-antibiotic P/S, HEPES, a non-essential amino acid solution, GlutaMax, human recombinant protein EGF, human recombinant protein bFGF, human recombinant Macrophage stimulating protein (MSP), cortisol, B27, Insulin, Transferrin, Selenium, Ethanolamine Solution (ITS-X), and an Advanced DMEM/Fl2 medium.
However, the prior art of Sachs discloses a culture medium for epithelial cells with improved culture methods for expanding epithelial cells (See e.g. abstract, para. 15-26, 296, 478)
Regarding claim 25, medium, Sachs discloses a medium with penicillin/streptomycin (see e.g. para. 105, fig. 14), HEPES is 10mM (para. 639-640), about 1% GlutaMax (e.g. para. 104, 196-197, 639-640), and non-essential amino acids: glycine, L-alanine, L-asparagine, L-aspartic acid, L-glutamine acid, L-proline, and L-serine (see e.g. para. 197 and 306) with water. Sachs discloses a medium with human recombinant protein EGF at a range of 10-100 ng/mL (e.g. 50 ng/ml), human recombinant protein bFGF 10-50 ng/mL(e.g. 50 ng/ml); (see e.g. para 137-148, claim 15). Sachs discloses the culture medium further comprises a final concentration of the B27 about 1% (volume percentage)(500mM) and B27 supplement may be formulated to comprise insulin, transferrin, selenium (see e.g. para. 104, 180-183). Further, Sachs discloses a medium that consists of Advanced DMEM/Fl2 medium (para. 103-104).
In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate a cell medium as taught by Sachs with a reasonable expectation of success. A person of ordinary skill art would have done so because Sachs discloses that the medium allows for “enhanced ability to obtain more cells from a small collection of starting cells is advantageous for applications where little starting material is available, such as biopsies of primary cancer” (para. 66). Furthermore, a person of ordinary skill in the art could have arrived at the concentrations by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Moreover, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 25, as discussed above, Sachs discloses the non-essential amino acids: glycine, L-alanine, L-asparagine, L-aspartic acid, L-glutamine acid, L-proline, and L-serine (see e.g. para. 197). Further Sachs discloses that “generally, each amino acid when present is present at about 0.001 to about 1 g/L of medium (i.e. 1% volume percentage) which reads on the claim limitation of an amino acid solution is 0.8-1.2% (volume percentage).
Sachs does not explicitly state each non-essential amino acid having a concentration of 10mM.
Nevertheless, the MPEP § 2144.05 (II) states, "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. lnc.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 lnt'I 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.").
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate a cell medium with a non-essential amino acid solution comprising components each with 10mM concentration as taught by Sachs because Sachs discloses that “generally, each amino acid when present is present at about 0.001 to about 1 g/L of medium (i.e. 1% volume percentage) which reads on the claim limitation of an amino acid solution is 0.8-1.2% (volume percentage). Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success because Sachs discloses A person of ordinary skill art would have done so because Sachs discloses that the medium allows for “enhanced ability to obtain more cells from a small collection of starting cells is advantageous for applications where little starting material is available, such as biopsies of primary cancer” (para. 66). Furthermore, a person of ordinary skill in the art could have arrived at the concentrations by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Moreover, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 25, medium, as stated supra, Sachs discloses and B27 supplement may be formulated to comprise insulin, transferrin, selenium (see e.g. para. 104, 180-183). Sachs does not explicitly state a solution of Insulin, Transferrin, Selenium, Ethanolamine Solution (ITS-X) is 0.8-1.2% (volume percentage), or a final concentration of the cortisol is 20-50 ng/mL.
However, the prior art of Herreno discloses cell culture methods for a primary lung cancer cell culture (See e.g. abstract, pages 1-3, Table 1).
Regarding claim 25, medium, Herreno discloses a primary lung cancer cell culture with a medium comprising Insulin is 5 μg/ml, Transferrin is 5 μg/ml sodium selenite (i.e. selenium) is 30nM, and Ethanolamine (10 μM), which reads on the claim limitation of Insulin, Transferrin, Selenium, Ethanolamine Solution (i.e. ITS-X) is 0.8-1.2% (volume percentage)(see page 4, Table 1). Further, Herreno discloses the medium comprises 100nM of hydrocortisone (i.e. cortisol).
In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu with a cell culture medium comprising ITS-X and cortisol as taught by Herreno because both Liu and Herreno discloses successful culture methods of primary lung cancer patients. A person of ordinary skill in the art would have had a reasonable expectation of success because Herreno discloses a successful experimental model for studying primary culture of human lung tumor cells from patients. Further Herreno discloses that the culture methods are an “initial approach to our long-term goal of establishing immortalized lung cancer cell lines from Colombian patients that will allow the study of tumor biology in our population and impact current treatments” (See e.g. page 12). Additionally, a person of ordinary skill in the art could have arrived at the ITS-X and cortisol concentration by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Furthermore, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 25, medium, Liu and Sachs are silent regarding Macrophage stimulating protein (MSP) and the final concentration of the human recombinant protein MSP is 5-25 ng/mL.
However, the prior art of Willett discloses cellular function of lung tumor cell lines cultured with MSP (concentration at 1nM, 3nM, and 5nM, see e.g. page 491) and Yoshimura discloses culturing with MSP the corresponds to 15ng/ml of natural MSP, corresponding to the claim limitation of human recombinant protein MSP is 5-25 ng/ml (see e.g. page 15466, fig. 7).
In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu with a cell culture medium comprising Macrophage stimulating protein (MSP) as taught by Willett and Yoshimura because Willett discloses culturing a carcinoma cell line with MSP resulted in increased motility in a cell-migration assay, suggesting that MSP might promote cell migration of some lung tumors. Therefore, it would have been obvious for a person of ordinary skill in the art to have a culture medium with MSP to keep cells viable for cell culture studies regarding testing cancer drug treatments. Additionally, a person of ordinary skill in the art would have had a reasonable expectation of success because Yoshimura discloses the concentration of 15 ng/ml would be an optimal natural MSP concentration in a cell medium, as discussed above. Additionally, a person of ordinary skill in the art could have arrived at the MSP concentration by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Furthermore, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 25, medium, Liu et al., is silent regarding the final concentration of penicillin is 100-200 U/mL and streptomycin is 100-200 μg /mL in the dual-antibiotics P/S, and the dosage of 0.1-0.3 mL of sample dissociation solution per 1 mg of tissue with the cell isolation buffer comprises a dual- antibiotics P/S (Penicillin-Streptomycin), heparin sodium, and the final concentration of the heparin sodium is 10 IU/mL.
However, as stated supra, Sachs discloses a phosphate buffer saline (PBS) in a dissociation solution and 5ml of “Penicillin/Streptomycin 10K U/ml 10K μg/ml 100x” (see e.g. Figure 14) and heparin (see e.g. page 308). Further, the prior art of Herreno discloses 1% streptomycin/penicillin (see e.g. page 3), and Inoue discloses “1% Pen and Strep (both 100 units/ml) and 100 μg/ml as concentrations”(see e.g. page 8).
Although Sachs et al., do not explicitly state the final concentration of the heparin sodium is 10 IU/mL. Nevertheless, the prior art of Bray discloses 0.1 mg/mL (i.e. 10 IU/mL) of heparin facilitated the extraction of fibronectin tissue from lung parenchyma (see e.g. abstract).
In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate a cell solution with dual- antibiotics P/S (Penicillin-Streptomycin), heparin sodium as taught by Sachs, Herreno, Inoue and Bray with a reasonable expectation of success. As discussed above, a person of ordinary skill in the art would have had a reasonable expectation of success because Sachs discloses a medium with the enhanced ability to obtain more cells from a small collection of starting cells (para. 66), and Herreno discloses a successful experimental model for studying primary culture of human lung tumor cells from patients (See e.g. abstract). Additionally, Inoue discloses cell culture methods for cancer tissue obtained from individuals into single cells (see e.g. claim 2). Furthermore, Bray discloses heparin aids in cell culture methods of tissues from the lung (see e.g. abstract, fig. 1, page 793). Furthermore, a person of ordinary skill in the art could have arrived at the concentration by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Moreover, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 25-26, as stated supra, Liu discloses dissociating solid tumor tissues of lung cancer with a sample dissociation solution to obtain primary cells from solid tumor of lung cancer (see e.g. page 12 and 28 and claim 1). Further, Liu discloses wherein the sample dissociation solution preheated to 37° C in advance, for about 15 minutes to 3 hours (see e.g. page 26). Further, Liu discloses cutting the solid tumor tissues of lung cancer (see e.g. page 25, Example 1).
Regarding claim 32, Liu is silent regarding the sample having a diameter of 80-120 μm.
However, the prior art of Sachs discloses passaging samples having an average size of 100-200 μm (see e.g. para. 403).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate passaging a cell size as taught by Sachs because Sachs discloses an average cell size of average size of 100-200 μm (see e.g. para. 403). According to MPEP 2144.05(I), “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) . . . Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).” A person of ordinary skill art would have had a reasonable expectation of success because Sachs discloses methods that contain a medium that allows for “enhanced ability to obtain more cells from a small collection of starting cells is advantageous for applications where little starting material is available, such as biopsies of primary cancer” (para. 66). Moreover, an artisan of ordinary skill in the art of (i.e. cancer cell culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 35, Liu discloses a defined DMEM/F12 medium see e.g. page 15, fig. 12) Further, Liu discloses preparing a drug solution in a final concentration of DMSO (see e.g. fig. 6).
However, Liu is silent regarding wherein the volume ratio of the Advanced DMEM/Fl2 medium, the DMSO and the 1% methylcellulose solution is 20:2:(0.8-1.2).
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
Nevertheless, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate the cryopreservation solution as taught by Timmins with a reasonable expectation of success. A person of ordinary skill in the art could have arrived at the concentration by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Furthermore, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Liu et al., is silent regarding cryopreserving the cells after 2-3 passages.
However, the prior art of Timmins discloses that the combination of a dissociated reagent (typically an enzyme) and the fluid and shear forces effected by repeated passage of the suspension through the aperture of a pipette tip breaks apart cell aggregates (see e.g. para. 42-44). Timmins discloses terminating a dissociation reaction with the digestion termination solution and collecting a cell suspension; filtering the cell suspension to remove tissue debris and adherent cells; centrifuging and then resuspending cells with sterile PBS; centrifuging again and resuspending the cell precipitation. (see e.g. para. 29, 67, Table 1, Example 1).
Regarding claim 35, the prior art of and Timmins discloses passaging the aggregates over five passages (i.e. after 2-3 passages) and that the that the full cell culture may be washed and utilized for an end product, such as cryopreserved product (See e.g. page 22).Further, Timmins discloses cell digestion solution for the passage is as follows: each 10 mL of the cell digestion solution contains 50% Accutase, EDTA and 4 mL of TrypLE Express, and the rest is PBS (see e.g. page 13).
According to MPEP 2144.05(I), “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) . . . Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate a number of passages as taught by Timmins with a reasonable expectation of success. A person of ordinary skill in the art could have arrived at the concentration by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Furthermore, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant asserts that Liu focuses on a specific method using ROCK inhibitors and does not disclose or suggest the inclusion of MSP, ITS-X, or Cortisol (Remarks, page 16). Applicant argues that a person of ordinary skill in the art would not combine Liu and Sachs because Sachs does not teach MSP or cortisol in the medium(Remarks, page 16). Further, Applicant argues that a person of ordinary skill in the art would not combine Liu and Herreno because Herreno uses traditional serum-containing medium and lacks the “two key modern components of the medium defined in the pending claims MSP and the ROCK inhibitor (Y-27632)”(Remarks, page 16).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on July 11, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments against the references of Liu, Sachs, and Herreno, 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, Liu is cited for teaching patient-derived, primary epithelial tumor cells from cancer-tissue originated spheroids (CTOSs) (see e.g. abstract). It is noted that Applicant argues that Liu focuses on a specific method using ROCK inhibitors. However, Applicant then argues that “two key modern components of the medium defined in the pending claims MSP and the ROCK inhibitor (Y-27632)”(Remarks, page 16). Therefore, in response to applicant's argument that Liu would not be combined with the other references, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, the prior art of record Liu, Sachs, and Herreno disclose primary lung cancer cells. Further, it is noted that Applicants independent claim recites “comprising the following steps,” and therefore does not exclude other steps or elements. Furthermore, in response to Applicants argument regarding Herreno there is not a claim limitation directed to serum-free medium, and the claim is directed to a method of culturing primary tumor cells from lung cancer (see claim 25).
Applicant argues the combination of Liu with Willett/Yoshimura because Willett' s work only investigated the effects of MSP on cell migration and signaling pathways in existing cell lines (such as A549) (Remarks, page 17). Further, Applicant argues that the prior art of Inoue and Bray are irrelevant to the core components of the culture medium (Remarks, page 17). Applicant asserts that the prior art references or any combination thereof are not sufficient to teaching or suggesting the specific culture medium composition recited in the pending claims (Remarks, page 17).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments against the references of Liu, Willett/Yoshimura, and Inoue and Bray 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, Willett/Yoshimura, and Inoue and Bray are not cited for pleural effusion, the prior art of Liu is cited for disclosing a patient-derived, primary epithelial tumor cells from cancer-tissue originated spheroids (CTOSs) that are obtained from a pleural effusion sample (i.e. primary tumor cells from pleural effusion of lung cancer) (see e.g. abstract and claim 2). In response to applicant's argument that Inoue and Bray are irrelevant to the core components of the culture medium, the prior art of Inoue and Bary are not cited for teaching the core components (MSP, ITS-X, B27, Cortisol). In response to applicant's argument that Willett' s work only investigated the effects of MSP on cell migration and signaling pathways in existing cell lines (such as A549), the A549 cell line is a type II pulmonary epithelial human cell line which is a model for lung cancer. Furthermore, as stated supra, Yoshimura is also disclosed for culturing with MSP the corresponds to 15ng/ml of natural MSP, corresponding to the claim limitation of human recombinant protein MSP is 5-25 ng/ml (see e.g. page 15466, fig. 7). Contrary to Applicants argument the prior art references do not span different technical fields and all relate to cancer cell culture and lung tumors.
Applicant argues that that “the present application, for the first time, combines MSP, ITS-X, a specific high concentration of B27, Cortisol, and Y-27632 at precise concentrations, unexpectedly solving the technical challenge of culturing and maintaining primary lung cancer pleural effusion cells in vitro. This combination yields significantly superior results compared to the closest prior art, thus demonstrating the non-obviousness of the present application”(Remarks page 17). Further, Applicant argues against the Offices reasoning of “routine optimization” and “obvious to try” regarding the concentration of the components noting that “particular parameters being optimized must first be recognized as a result-effective variable” (Remarks, page 18).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
It is noted that Applicants arguments amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. Furthermore, it is noted that Applicant has not argued or submitted an affidavit indicated how Applicants claims yields significantly superior results compared to the closest prior art (i.e. Liu).
In response to applicant's argument regarding an effective variable, and the reasoning of “routine optimization and “obvious to try”, the MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”. In the instant case, it would have been obvious to a person of ordinary skill in the art of culturing cells that the culture medium effects the culturing and maintaining primary lung cancer pleural effusion cells in vitro, absent evidence to the contrary.
Applicant asserts that the Embodiment 28, Table 31, shows importance of the cell cultures components and ratios (Remarks, page 19). Applicant argues that Table 33 demonstrates that the specific formulation of the cell digestion solution (the specific ratio of Accutase, EDTA, and TrypLE Express) is crucial for successful cell passaging (Remarks, page 19).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments of significant and unexpected results, it is noted that in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
In the instant case, it is understood that Embodiment 28, Table 31, shows importance of the cell cultures components and ratios and that the specification recites that Table 31 is dependent on the cell culture medium from Table 8, which encompasses the claim limitation recited in claim 25. However, Applicants unexpected results are supported by Scheme D (i.e. 85% success rate), which uses the formula used in Table 6 having Accutase, EDTA, TrypLE Express, and PBS (see specification para. 129 and 352), which are not recited in claim 25. Therefore, Applicants arguments are not commensurate in scope with the claimed method. Further, it is noted that Table 33, Scheme D, is directed to cell passaging. Further, it is noted that there is not a claim limitation in the independent claims that is directed to passaging more than 6 times, and it is not clear how this compares to the cited prior art.
Applicant argues Table 34 and 35 show the significant impact and success rate of CYTOP modifications. Applicant asserts unexpected results achieved with and the significant technical contribution having a “dramatic decrease in culture success rate from, e.g., 70-85% to 0-20%” (Remarks, page 19).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
It is noted that applicant asserts Table 34 and 35 show the significant impact and success rate of CYTOP modifications. However, it is noted that table 35, hast two samples failed testing with all the different testing materials (see Spec. Embodiment 30, para. 360, Table 35). Further, it is noted that Table 34 does not have one material that passes every sample. Therefore, it is unclear what impact and success rate of the CYTOP modification that Applicant is referring to in the specification.
It is noted that Applicant argues a decrease in culture rate “from, e.g., 70-85% to 0-20%,” (Remarks, page 19). However, it is unclear what result from the specification is being referring to since no citation is made (see page 19). If Applicant is referencing to the success rate of table 34, where the low-attachment surface (LAS) is the highest (see spec. para. 358) then it is noted that LAS is made from table 36 (spec. embodiment 30-31). However, it is unclear how the results are significant or unexpected since they are not commensurate in scope with the claims (i.e. low-attachment surface (LAS)) and is not being compared to the closest prior art.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claims 27 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al., (WO2018094410A1, published 2018, prior art of record), Sachs et al., (US2017/0275592A1, published 2017, prior art of record), Herreño, et al. (Cogent Medicine 5.1: 1503071, published 2018, hereinafter as “Herreno”, prior art of record), Willett et al. (American journal of respiratory cell and molecular biology 18.4: 489-496, published 1998, prior art of record), Yoshimura et al. "(Journal of Biological Chemistry 268.21: 15461-15468, published 1993, prior art of record), Inoue et al., (WO2011068183A1, published 2011, prior art of record), Timmins, et al., (WO2017127921A1, published 2017, prior art of record), and Bray et al., (Science 214.4522: 793-795, published 1981, prior art of record), as applied to claims 25-26 and 29-40 above, and further in view of Wu, Han, et al. (Small 14.38: 1802128, published 2018, prior art of record), Leosson, Kristjan, and Björn Agnarsson (Micromachines 3.1: 114-125, published 2012, hereinafter as “Leosson”, prior art of record), Ono et al., (Journal of applied physics 105.1, published 2009, prior art of record), and Polanco, et al. (JoVE 139: 58296, published 2018, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on July 11, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Liu et al. apply here as discussed above.
Regarding claims 27, as stated supra, Liu et al., discloses culturing primary tumor cells from pleural effusion of lung cancer are suspension-cultured with a cell culture medium (see Liu e.g. abstract, page 2, 10, 22, 28 and claim 1-2, 9, and 20).
Liu is silent regarding replacing the cell culture medium every 2-4 days until the cell masses with a diameter of 80-120 μm are formed.
However, the prior art of Sachs discloses passaging samples having an average size of 100-200 μm (see e.g. para. 403). Further Sachs discloses replacing the cell culture medium every 2-4 days (see e.g. para. 401).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate passaging a cell size as taught by Sachs because Sachs discloses an average cell size of average size of 100-200 μm (see e.g. para. 403). Furthermore, it is noted that "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944). Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success because Sachs discloses methods that contain a medium that allows for “enhanced ability to obtain more cells from a small collection of starting cells is advantageous for applications where little starting material is available, such as biopsies of primary cancer” (para. 66). Moreover, an artisan of ordinary skill in the art of (i.e. cancer cell culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 27-28, as stated supra, Liu et al., discloses culturing primary tumor cells from pleural effusion of lung cancer are suspension-cultured with a cell culture medium (see Liu e.g. abstract, page 2, 10, 22, 28 and claim 1-2, 9, and 20). Additionally, Liu discloses suspension-culturing the dissociated primary cells from solid tumor of lung cancer and incubated at 37°C on low-cell binding plates (i.e. low adsorption surface) (see e.g. page 28, claim 1 and reprogramming single cell cultures).
Liu et al., is silent regarding the humidification of the cell culture vessel M and having culture conditions of the medium changed every 4 days and the conditions being humidified at 37° C and 5% CO2.
However, Sachs discloses culture conditions of medium changed every 4 days and the conditions being humidified at 37° C and 5% CO2 (see e.g. para. 626), and that the vessel may be any suitable vessel, such as a flask, a plate, a bottle, a jar, a vial or a bag.).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate the culture conditions for the cell medium as taught by Sachs with a reasonable expectation of success. A person of ordinary skill art would have done so because Sachs discloses that the medium allows for “enhanced ability to obtain more cells from a small collection of starting cells is advantageous for applications where little starting material is available, such as biopsies of primary cancer” (para. 66). Furthermore, a person of ordinary skill in the art could have arrived at the conditions and concentrations by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Moreover, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 27-28, Liu et al., is silent regarding the cell culture vessel M with an etching power of 20W for 3mins and being covered with a 1% CYTOP solution, fluorocarbon oil, and drying the CYTOP solution in the air to complete the CYTOP modification.
However, the prior art of Wu discloses using a single cell array with about 1% CYTOP solution where the hydrophobic amorphous fluoropolymer, CYTOP was spin-coated on the cleaned glass slide at 1000 rpm for 30 s and the coated substrate was then air dried for 10 min to evaporate most of the solvent (see e.g. pages 6-7, fig. 1, 2-3, 8), corresponding the claim limitation of drying the CYTOP solution in the air to complete the CYTOP modification. Further the prior art of Leosson discloses that CYTOP is a soluble fluorinated solvent (i.e. fluorocarbon oil) that can be cast into thin films (see e.g. page 114-116), which reads on the claim limitation where the rest is fluorocarbon oil.
Further, MPEP § 2144.05 (II) states, “Generally, differences in time, 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.”).
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed time is critical, thus the teaching of 10 mins as renders the claimed time period obvious.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate the CYTOP modifications as taught by Wu and Leosson with a reasonable expectation of success, because Leosson discloses that “CYTOP plays a crucial role in extending the range of possible penetration depths of the excitation field, controlled by varying the waveguide core layer thickness and/or refractive index. For the same reason, so-called reverse symmetry waveguides fabricated on special low-index porous glass substrates have been developed and used for refractive index sensing, as well as bacterial and cell monitoring applications”( page 118). Further, Leosson discloses that “CYTOP has a unique refractive index that enables the cladding material to be well index-matched to an optically probed sample solution. Furthermore, ultra-high index contrast waveguides can be fabricated, using conventional optical polymers as waveguide core materials” (see e.g. 114). Moreover, a person of ordinary skill in the art could have arrived at the concentration by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Furthermore, an artisan of ordinary skill in the art of (i.e. cell monitoring application) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Although Wu and Leosson do not explicitly state an etching power of 20W for the CYTOP modification.
Nevertheless, the prior art of Ono discloses etching using the amorphous fluoropolymer (i.e. CYTOP) with an etching power of about 8W (see e.g. abstract, pages 1-2) and discloses an etching range of 30 second to 6 mins (see e.g. fig 4).
According to MPEP 2144.05(I), “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) . . . Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.’)”.
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed watts (i.e. power) and time is critical, thus the teaching of a time range and of 8W renders the claimed power as obvious.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to modify the methods as taught by Liu and incorporate the CYTOP modification with the optimal etching power as taught by Ono to the etched surface because Ono discloses that CYTOP is the preferable fabrication material because of its excellent stability (see e.g. abstract). Therefore, a person of skill in the art would have had a reasonable expectation of success of applying the CYTOP modification to the methods of Liu. Furthermore, the prior art of Polanco discloses that it was known in the prior art to use of a low refractive index polymer such as CYTOP for biomedical microfluidics. Additionally, a person of ordinary skill in the art would have done so because Polanco suggests that “an important challenge facing the combination of microfluidics with various microscopy techniques is the mismatch between the refractive index of the device material relative to the refractive index of water. One method to address this is through the use of a low refractive index polymer such as CYTOP” (page 1). Thus, providing a person of skill in the art to incorporate a CYTOP modification. Moreover, a person of ordinary skill in the art could have arrived at the etching power and time period by routine optimization and the disclosure does not point to a criticality in these concentration (see MPEP 2144.05(II)). Furthermore, an artisan of ordinary skill in the art of (i.e. tissue culture) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the prior art references are directed to Wu, Ono, and Polanco belong to different technical fields and are not relevant to the field of cell culture (Remarks, page 20).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments against the references of Wu, Ono, and Polanco 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 prior art of Wu, Ono, and Polanco all relate to the use of the cyclic transparent optical polymer, CYTOPTM, with surfaces that impact cells. The prior art of Ono discloses that transparent material (i.e. CYTOP) has significant advantages in cell analysis on devices or imaging (see e.g. page 105). Further, the prior art of the prior art of Wu and Polanco disclose CYTOP’s impact with cell culture surfaces (see e.g. 5-6, and 1, respectively). Therefore, a person of ordinary skill in the art (i.e. in the field of cell culture) would recognize that the transparent properties of CYTOP would be advantageous for cell analysis and imaging. Therefore, Applicants arguments that the secondary reference are not relevant to the field of cell culture is unpersuasive.
Applicant argues that the prior art of Wu is directed to promoting cell fixation and the present invention is directed to preventing cell adhesion (Remarks, page 20). Applicant asserts that neither Ono nor Polanco teach using CYTOP to treat cell culture surfaces (Remarks, page 20).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument regarding Wu, it is noted that promoting cell fixation does not include a citation directed to Wu or the specification. As stated above, the prior art of Wu discloses using a single cell array with about 1% CYTOP solution. Further, it is noted that even if Wu was directed to promoting cell fixation, Wu also discloses that the cells did not adhere to the hydrophobic CYTOP surface (see e.g. page 6). Therefore, as states supra, a person of ordinary skill in the art would know that the main advantage of using CYTOP would be for its transparency as a thin-film coating (see e.g. page 7).
In response to Applicants argument that neither Ono nor Polanco teach using CYTOP to treat cell culture surfaces, the prior art of Wu was cited for teaching CYTOP with cell culture surfaces (see e.g. 5-6). As discussed above, the prior art of Wu, Ono, and Polanco all relate to the use of the cyclic transparent optical polymer, CYTOPTM, with surfaces that impact cells. The prior art of Ono discloses that transparent material (i.e. CYTOP) has significant advantages in cell analysis on devices or imaging (see e.g. page 105). Further, the prior art of the prior art of Wu and Polanco disclose CYTOP’s impact with cell culture surfaces (see e.g. 5-6, and 1, respectively). Therefore, a person of ordinary skill in the art (i.e. in the field of cell culture) would recognize that the transparent properties of CYTOP would be advantageous for cell analysis and imaging. Therefore, Applicants arguments that the secondary reference are not relevant to the field of cell culture is unpersuasive.
Applicant argues that the composition and proportions are directed to serum-free cell cryopreservation solution (i.e. claim 35), whereas Liu discloses a conventional cryopreservation solution containing serum (Remarks, page 20).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicant argues that claim 35 specifically defined the composition and proportions of serum-free cell cryopreservation solution, Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
In the instant case, contrary to Applicants assertion the claim 35 does not recite a limitation directed a serum-free cell cryopreservation solution. Furthermore, it is noted that claim 34 discloses a digestion termination solution comprising fetal bovine serum.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631