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 on Sept. 17, 2018, and is a 371 application of PCT/CN2016/076703 filed on March 18, 2016. The effective filing date for the claims is March 18, 2016.
Status of the Claims
In the response filed August 12, 2025, Applicant has amended claims 37, and 131, and cancelled claims 3-8, 11-16, 18-19, 21-26, 28-36, 38-49, 51-59, 61, 63-76, 78-82, 84-93, 95-113, 117-120, 122, 124-125, and 127-128, and claims 1-2, 9-10, 17, 20, 27, 77, 83, 94, 114-116, 121, 123, and 126 have been withdrawn from consideration as being drawn to non-elected subject matter.
Currently, Claims 37, 50, 60, 62, and 129-132 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Sept. 4, and Oct. 21, 2025, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment.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
Claim 37 is objected to because of the following informalities: typographical error on last line of the claim, where “mg/mL mg/mL” is recited twice in the sentence. 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 37 and 131 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 applicant’s amendments to the claims submitted on 12 of August 2025.
Regarding claim 131, the claim recites “said insulin has a level ranging of 4 mg/L, said transferrin has a level ranging of 5 mg/L, said sodium selenite has a level ranging between 16 μg/L”, however it is not clear what range is being presented in the claim. A person of ordinary skill in the art would not be able to determine that range since the claim does not recite an upper or lower limit to the range (e.g. insulin ranging from 1mg/L to 4mg/L). Therefore, it is not apparent how one can have a level range of 4mg/L because one cannot determine the upper limit or lower limit of the range. Also, the “level ranging between” does not indicate another amount that the 16μg/L of sodium selenite is being compared to in the claim. Therefore, a person of ordinary skill in the art would not know if the 16μg/L is the upper limit or the lower limit of the range of sodium selenite. Therefore, the parameters regarding the amounts of the insulin, transferrin, and sodium selenite have been rendered indefinite because a range has not been indicated.
In order to expedite prosecution, the claimed level range of insulin and transferrin will be ranging from about 0.04 mg/L to about 500 mg/L (see Spec. support para. 89) and the claimed level range of sodium selenite will be ranging from 0.16 μg/L and about 1600 μg/L (see Spec. support para. 90). Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 37, 50, 60, 62 and 129-132 are rejected under 35 U.S.C. 103 as being unpatentable over Chen356 (WO2015/042356; prior art of record) in view of Wang et al., (WO2016/022992A1, published Feb. 11, 2016), Wang, Xiaowen, et al. ("Scientific reports 6.1: 23017, published March 15, 2016, hereinafter as “Wang, Xiaowen”), Burridge, Paul W., et al. (Nature methods 11.8: 855-860, published 2014), Mitalipova et al. (WO2011/142832; prior art of record), Huang, (J Agric Food Chem 1996, 2:444-452, prior art of record), and Peng, et al., (Pediatric research 70.1: 61-66, published 2011), Zimmermann et al. (WO 2015/040142 A1, PCT/EP2014/069951, published 2015, prior art of record), Xu et al. (Stem cells and development 15.6: 931-941; published 2006, prior art of record), Duanqing Pei et al. (US2013/0040390A1, published 2013, prior art of record), and Parenteau et al. (US 2006/0121605, Appl. No.: 10/559,474, published 2006, 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 Dec. 10, 2024, 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 claim 37 and 131, Chen356 discloses a substantially albumin-free cell culture medium (i.e. low-protein medium)(see e.g. E8 medium, page 2, 6, 13-14, and 15), which culture medium comprises antioxidants L-ascorbic acid (i.e. ascorbic acid)(see e.g. page 19), and pyruvic acid (see e.g. Table 1 at page 12). Chen356 discloses a cell culture medium with DMEM/F12 (see e.g. page 12 and 19-20), vitamins (see e.g. page 12), and no albumin (i.e. substantially albumin-free)(see e.g. page 12, 19-20, Example 1), which reads on the claim limitation of less than 1x10-4mg/mL albumin. Further, Chen356 discloses L-ascorbic acid (i.e. ascorbic acid) has a level of 64mg/L (i.e. 0.064mg/mL)(see e.g. page 19), pyruvic acid (see e.g. Table 1 at page 12), selenium (i.e. sodium selenite) at a level of 14ug/L, transferrin at a level of 10.7mg/L (i.e. 0.0107 mg/mL)(see e.g. page 19), and NaCH03 (i.e. salt) and a lipid mixture of linoleic acid and linolenic acid(see e.g. pages 2, 7, 12-14, 20,). Additionally, Chen356 discloses methods for generating cardiomyocytes from stem cells (e.g. embryonic stem cells and induced pluripotent stem cells (iPSC))(see e.g. page 27, fig. 19).
Regarding claim 37 and 131, as stated supra, Chen356 discloses a low-protein (i.e. albumin-free) culture medium that may comprise 20mg/L of insulin (see e.g. page 19), and selenium (i.e. sodium selenite) at a level of 14ug/L. While Chen356 discloses that certain factors can be removed from the low protein medium, such as insulin (see e.g. page 14, last para., pg. 1, ln. 14-24; pg. 15, lines 17-20; pg. 29, claim 1, 32), Chen356 also discloses that insulin may be present for cardiomyocyte maturation and maintenance (see e.g. fig 11, 14).
Chen is silent regarding insulin having a level ranging between 0.002mg/mL and 0.02mg/mL
However, the prior art of Wang discloses culture medium for cardiomyocytes with insulin-transferrin-selenium (i.e. ITS), and ascorbic acid in methods for somatic cell-reprogramming and cardiomyocyte reprogramming (see e.g. abstract, para. 5, 50, 75-79). Further, Wang discloses insulin having a level range of 10nM to 10 mM (see e.g. para. 5, 50, and formula table), which reads on the claimed range of 0.002 mg/mL (344nM) to 0.02mg/mL (34μM) and 4mg/L (689nM)(e.g. insulin is 5,800Da).
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify the method of Chen356 with the amount of insulin as taught by Wang because Wang discloses that Insulin-transferrin-selenium (ITS) was found to improve the reprograming of fibroblast into cardiomyocytes through a pluripotent state (see e.g. para. 23 and page 9-13, 18, claim 16). Moreover, Chen356 also discloses that insulin may be present for cardiomyocyte maturation and maintenance (see e.g. fig 11, 14). Additionally, the prior art of Wang, Xiaowen (2016), same inventor/author, discloses that the removal of insulin-transferrin-selenium completely inhibited the effect of reprogramming media upon cardiac gene expression (see e.g. abstract, page 8). Thus, it would have been obvious for a person of ordinary skill in the art to have insulin present in the cell culture medium. Thus, a person of ordinary skill in the art would have a reasonable expectation of success for adding insulin as taught by Wang to the albumin-free cell culture medium as taught by Chen356 in order to obtain cardiomyocytes.
Regarding claim 37 and 131, as discussed above, the limitation directed to the additional ingredients and level of ranges of the additional ingredients in the culture medium comprising transferrin, sodium selenite, linolenic acid and linoleic acid, Chen356 discloses L-ascorbic acid (i.e. ascorbic acid) at a level of 64mg/L (i.e. 0.064mg/mL)(see e.g. page 19), which reads on the claim limitation of ascorbic acid having a level ranging between 0.025mg/mL and 0.25 mg/mL. Further, Chen356 discloses selenium (i.e. sodium selenite) at a level of 14ug/L, transferrin at a level of 10.7mg/L (i.e. 0.0107 mg/mL)(see e.g. page 19).
Chen356 does not explicitly disclose the level of pyruvic acid ranging between 0.5mM and 5mM, ascorbic acid at a level of 50mg/L and ranging between 0.025mg/mL and 0.25 mg/mL, and sodium selenite at a level of 16ug/L.
However, as stated supra, the prior art of Wang discloses culture medium with insulin-transferrin-selenium (ITS) medium and supplements such as ascorbic acid and pyruvic acid in the culture medium for cardiomyocyte (see e.g. abstract, para. 5, 50, 75-79). Further, Wang discloses sodium selenite at a level of about 1 to 100 μg/L(i.e. 0.1ug/mL)(see e.g. para. 50), which reads on the claimed level of 16ug/L. Wang discloses pyruvic acid (i.e. sodium pyruvate) at a level of 11g/L (i.e. about 200mM)(see formulation table). Wang discloses ascorbic acid ranging from 500μM to 50mM (see e.g. para. 57) which reads on the claimed range between 0.025mg/mL (142μM) and 0.25 mg/mL (1.4mM) ascorbic acid at a level of 50mg/L (284 mM).
Wang does not explicitly disclose a level of pyruvic acid ranging between 0.5mM and 5mM.
However, 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) (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 concentration of pyruvic acid is critical, thus the teaching of pyruvic acid as taught by Wang renders the claimed concentration obvious.
Accordingly, it would have been obvious for a person of ordinary skill in the art to modify the method of Chen356 with the amount of ascorbic acid, sodium selenite, and pyruvic acid, as taught by Wang because Wang discloses methods for improving efficiency of reprogramming cardiomyocytes (see e.g. page 9, 13). Further, the prior art of Wang, Xiaowen (2016), same inventor/author, discloses that the removal of insulin-transferrin-selenium completely inhibited the effect of reprogramming media upon cardiac gene expression (see e.g. abstract, page 8). Thus, it would have been obvious for a person of ordinary skill in the art to optimize the amount of insulin-transferrin-selenium. A person of ordinary skill in the art would have a reasonable expectation of success for optimizing the amount of ascorbic acid, sodium selenite, and pyruvic acid, as taught by Wang to the albumin-free cell culture medium as taught by Chen356 in order to efficiently obtain cardiomyocytes.
Regarding claim 37 and 131, Chen356 teaches the low protein medium further comprises alpha-tocopherol (i.e. vitamin E) at 70mg/mL (see e.g. page 7, 14, claim 4).
Chen356 is silent regarding a water-soluble vitamin E analog having a level ranging between 0.025mM and 0.25mM or a level at 0.05mM.
However, the prior art of Burridge discloses 1 μg/ml of alpha-tocopherol (i.e. 2.3 micromolar)(i.e. vitamin E)(see e.g. online methods page 862)
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 concentration of vitamin E (i.e. Trolox) is critical, thus the teaching of vitamin E (i.e. Trolox) acid as taught by Burridge renders the claimed concentration obvious.
Accordingly, it would have been obvious to prepare a low-protein medium comprising water-soluble analog of vitamin E and substitute the alpha-tocopherol as taught by Chen356 and with the water soluble analog of vitamin E (i.e. Trolox) as taught by Burridge because Burridge discloses an efficient, reproducible, and scalable method for deriving cardiomyocytes from stem cells (see e.g. page 859). Further, the prior art of Mitalipova teaches that an antioxidant derivative has “a desired feature, such as increased water solubility, as compared with a compound of what it is a water-soluble derivate, such as Trolox” (para. 128, 135, and 142; Supp. Table 3). Further, the prior art of Mitalipova teaches a medium for the culturing of stem cells comprising the water-soluble analog of vitamin E, such as Trolox (i.e. vitamin E)(para. 128). Additionally, the prior art of Huang et al. (1996) teaches that in a medium comprising lipids (such as the medium of Chens), Trolox is a better antioxidant than the water insoluble alpha tocopheraol (see e.g. Abstract). Thus, the addition of the water-soluble analog of vitamin E would have been done with a reasonable expectation of success.
Regarding claim 37 and 131, Chen356 teaches the low protein medium comprising at least two antioxidants, but they are silent to N-acetyl-cysteine or glutathione or a salt or an ester thereof having a level ranging between 0.025mM(25μM) and 0.25mM(250μM) (or a level of 0.05mM).
However, the prior art of Xiaowen Wang (2016) teaches glutathione at 1mg/L (i.e. 3.25μM). Further, the prior art of Burridge discloses 2.5 ug/mL (8mM) of glutathione. Additionally, the prior art of Peng discloses a range of 0.25-2mM on a heart myoblast cell line (see e.g. abstract, and page 62).
Further, the following is noted from the MPEP: MPEP 2144.05: “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).” MPEP 2144.05(I) teaches “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, 227 USPQ 773 (Fed. Cir. 1985).” 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 the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration of N-acetyl-cysteine or glutathione at 0.5mM is critical, thus the teachings of Wang, Burridge, and Peng renders the claimed concentration of N-acetyl-cysteine or glutathione as obvious.
Accordingly, it would have been obvious to a person skilled in the art to use a combination of antioxidants known in the art including, glutathione, or N-acetyl-cysteine, along with ascorbic acid and pyruvate in the cell culture medium of Chen356 (see e.g. 13-15) because Chen356, Wang, Burridge, and Mitalipova teach adding the combination of antioxidants for the same purpose of supporting stem cell survival. A person of ordinary skill would have optimized for glutathione, or N-acetyl-cysteine because Mitalipova teaches that antioxidants help protect cells (i.e. stem cells) against oxidative stress (see e.g. para. 140, page 46-47). Further, Wang discloses that Selenium is a co-factor for glutathione peroxidase and other proteins and is commonly used as an antioxidant in cell culture media (page 18). Moreover, Mitalipova teaches that the types of antioxidants, including glutathione and N-acetylcysteine, are commonly used antioxidants for cell culture (para. 128). Therefore, it would have been obvious to combine the N-acetyl-cysteine or glutathione with the ascorbic acid and pyruvate of Chen with a reasonable expectation of success.
Regarding claim 37 and 131, Chen356 is silent regarding carnitine having a level ranging between 2mg/L and 20mg/L.
However, Zimmermann teaches producing pluripotent stem cells in an albumin-free media with carnitine (i.e. L-carnitine HCL), ranging from 0.4 to 40 μg/ml and 100 μg/ml (i.e. 0.4 to 40 mg/L; see e.g. Table 4; claim 1; pg 2, line 35; pg 4, line 14, pg. 6, line 25, pg. 7, line 2; pg. 9 para. 2; pg 11 para. 2 ).
Accordingly, it would have been obvious to a person skilled in the art to use the taught amount of carnitine as taught by Zimmermann with the culture medium of Chen356, because both teach culturing stem cells in albumin-free media. Chen356 also teaches that differentiation conditions that are established without fetal calf serum, and thus without the presence of animal pathogens, increases the chances of stem cell derived cardiomyocytes, which are then suitable for cardiomyocyte transplantation in patients with heart disease (see e.g. page 25). Further, Zimmermann teaches generating undifferentiated human embryonic stem cells under albumin-free supplement with carnitine and selenium (see e.g. pages 7, 15, 29, claim 9, fig. 9) is a comparable supplement to what is known in the art. Additionally, the prior art of Xu et al., (2006), teaches albumin-free culture conditions with carnitine are useful for future research efforts to identify factor and culture conditions that enhance cardiac cell survival and proliferation (see e.g. page 938-939). Further, Xu teaches that defined albumin-free medium with carnitine is highly desirable in avoiding serum lot to lot variations in their ability to induce differentiation and maintain cell growth (see page 938). Furthermore, in regard to the amount of carnitine taught by Zimmerman, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233. Therefore, the results of this modification would have led to predictable results with a reasonable expectation of success.
Regarding claim 37 and 131, Chen356 is silent regarding ethanolamine and at a level ranging between 0.01mg/L and 1mg/L and linolenic acid and linoleic acid having a level ranging between 0.0005mg/mL and 0.005mg/mL; linolenic acid and linoleic acid having a level of 1mg/L (i.e. 0.001 mg/mL).
However, Duanqing Pei teaches producing pluripotent stem cells in an albumin-free (i.e. serum free culture supplement, see e.g. abstract, para. 49, 57) medium and ethanolamine for induced pluripotent stem cells (see e.g. abstract, page 6, para. 60, Example 2) at a molar concentration of 0.016 mg/L to 1 mg/L to (see e.g. Table 2 and para. 29), which reads on the claim limitation of an ethanolamine level ranging between .01 mg/L to 1mg/L of ethanolamine as claimed. Further, Duanqing Pei discloses linoleic acid ranging from 0-4ug/mL, preferably 1ug/mL, which equals 0.001mg/mL (i.e. 1mg/L), which reads on the claimed linoleic acid level ranging between 0.0005mg/mL and 0.005mg/mL and linoleic acid having a level of 1mg/L (i.e. 0.001 mg/mL). Additionally, Duanqing Pei discloses linolenic acid having a level of about 0.1mg/mL (see e.g. table 1).
Duanqing Pei is silent regarding linolenic acid having a level of 0.001mg/mL (i.e. 1mg/L).
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) (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 concentration is critical, thus the teaching of linolenic acid as taught by Duanqing Pei renders the claimed concentration obvious.
Accordingly, it would have been obvious to a person skilled in the art to use the taught amount of ethanolamine, linolenic acid, and linoleic acid as taught by Duanqing Pei with the albumin-free culture medium of Chen356, because both teach culturing stem cells in albumin-free media. Further, Duanqing Pei generating induced pluripotent stem (iPS) cells with high efficiency (see e.g. abstract). Further, the prior art of Parenteau teaches that ethanolamine may be necessary in a albumin-free medium for progenitor cells (para. 60). Furthermore, M.P.E.P. 2144.05: 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). Therefore, the results of this modification would have led to predictable results with a reasonable expectation of success.
Regarding claims 37 and 129, Chen356 teaches that the culture medium supports maintenance, proliferation or differentiation of pluripotent stem cells (see e.g. page 11), and thus, meets the intended purpose/results of the claimed product.
Regarding claim 37 and 50, as discussed above, the culture medium of Chen356 is “albumin-free”, i.e. no albumin, and thus, the culture medium of Chen356 would meet the limitation of albumin being less than 1x10-5 mg/mL (see e.g. page 5, 8 and 11).
Regarding the kit of claim 60, Chen356 teach a kit comprising a low protein medium that supports the proliferation and differentiation of stem cells (see e.g. page 5).
Regarding the substance in the kit of claim 62, as discussed supra, Chen356 teach a kit comprising a low protein medium that supports the proliferation and differentiation of stem cells and comprising one or more of a growth factor modulator (see e.g. page 5). Chen356 defines the growth factor modulator as a factor that is added to the culture medium that supports cell proliferation or differentiation (see e.g. page 8), and thus, Chen356 meets the limitations of claim 62.
Regarding claim 130, Chen356 teaches a cell culture medium is configured to obtain a ventricular cardiac differentiation efficacy ranging from 60% to 90% when cardiac differentiated cells express CTNT (page. 26, Fig. 15). Note: Specification indicates that cardiac differentiation efficacy is determined by percentage of CTNT (see Specification page 58-59, Table 8).
Regarding claim 132, Chen356 teaches the use of methyl-1-beta-cyclodextrin as a volume expander in the low-protein medium (see e.g. page 2 and page 14).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal:
Applicant argues that the prior art Chen356, Mitalipova et al. and Zimmermann et al. do not teach the use of carnitine (Remarks, page 12-13).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. In response to Applicants arguments, the prior art of Chen356, and Mitalipova et al. are not cited for teaching carnitine. As discussed above, the MPEP: MPEP 2144.05: “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).” Therefore, the range as taught by Zimmermann reads on the claimed range of carnitine. Contrary to Applicants assertion Zimmermann discloses a range encompassing the level of the claimed range of carnitine (i.e. L-carnitine HCL), ranging from 0.4 to 40 μg/ml and 100 μg/ml (i.e. 0.4 to 40 mg/L; see e.g. Table 4; claim 1; pages 2, 4-7, 9 and 11), therefore the claimed range is considered obvious.
Applicant argues improper hindsight because Zimmermann teaches albumin and teaches a range of carnitine much wider than the claimed range (Remarks, page 14). Further, Applicant argues that Xu does not teach the level of carnitine (Remarks, page 15).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. As discussed above, contrary to Applicants arguments Zimmermann discloses a range encompassing the level of the claimed range of carnitine (i.e. L-carnitine HCL), ranging from 0.4 to 40 μg/ml and 100 μg/ml (i.e. 0.4 to 40 mg/L; see e.g. Table 4; claim 1; pages 2, 4-7, 9 and 11), therefore the claimed range is considered obvious.
In response to Applicants arguments, the prior art of Xu was not cited for teaching the level of carnitine. As stated above, Xu was cited for disclosing that a person of ordinary skill in the art would want to add carnitine to albumin-free culture conditions in order to enhance cardiac cell survival and proliferation (see e.g. page 938-939). Further, Xu teaches that defined albumin-free medium with carnitine is highly desirable in avoiding serum lot to lot variations in their ability to induce differentiation and maintain cell growth (see page 938).
Furthermore, in response to Applicants arguments, regarding Zimmermann and albumin, it appears that Applicants response is alleging that every teaching of the secondary references would be combined with the teaching of the primary reference. The inquiry is to consider the references whole and both Chen356 and Zimmermann, regardless of using albumin in the medium, teaches a cell culture medium suitable for pluripotent stem cells and cardiomyocytes, and they both use antioxidants for the medium. Additionally, there is no teaching in Chen356 and Zimmermann that teaches that carnitine (i.e. L-carnitine HCL) is only used when albumin is present in the medium. Furthermore, the combining of known antioxidants that have been used in the culture medium suitable for pluripotent stem cells as taught by Chen356 and Zimmermann would have made it obvious for a person of ordinary skill in the art to try one antioxidant for another.
Applicant argues that there is no motivation to combine the cited art to arrive at the cell culture medium of claim 37. Further, Applicant argues that Zimmermann teaches away because the medium contains albumin (Remarks, page 16). Applicant asserts that a skilled artisan would not have any motivation to combine Chen356 with Zimmermann (Remarks, page 17).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. The Examiner respectfully disagrees with the applicant’s argument. One skilled in the art would recognize that the antioxidants used in Chen356 and those listed in Wang et al., Wang, Xiaowen, et al., Burridge, Paul W., et al., Mitalipova et al., Huang, Peng, et al., Zimmermann et al., Xu et al., Duanqing Pei et al., and Parenteau et al. are art-recognized equivalents. There is no teaching away for one skilled in the art to use known antioxidants for the same purpose of reducing oxidation in the culture medium. The rationale of combining the references is not based on the medium of Zimmermann, rather solely to the teaching directed to antioxidants being used in the cell culture medium for pluripotent stem cells. Regardless the method and/or culture medium taught by Zimmermann, the antioxidants listed in these secondary references would function as they are intended for. Further, the combined teachings are not based on the method of Zimmermann since the culture medium of Chen356 is modified by using other types of antioxidants along with those taught by Chen356 based on the combination of art-recognized equivalents for the same purpose as antioxidants. Therefore, it is the examiner’s position that the combined teachings would render the claimed invention obvious.
Applicant argues improper hindsight regarding carnitine and albumin the culture media in view of the prior art of Chen356, Mitalipova et al., and Zimmermann et al., and the Applicant further argues that because Zimmermann discloses the use of albumin that the Examiner has used impermissible improper hindsight (Remarks, page 18).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Zimmermann teaches albumin-free supplement with carnitine and selenium (see e.g. pages 7, 15, 29, claim 9, fig. 9). Contrary to Applicants argument, the supplement of carnitine is a known medium supplement in the art. Therefore, the knowledge is not coming from the applicant’s disclosure but the prior art shows that a person of ordinary skill in the art would have knowledge of carnitine and albumin free media.
As discussed above, Zimmermann teaches generating undifferentiated human embryonic stem cells under albumin-free culture (i.e. serum-free supplement) with carnitine and selenium (see e.g. pages 7, 15, 29, claim 9, fig. 9), which is a comparable supplement to what is known in the art. Additionally, the prior art of Xu et al., (2006), teaches albumin-free culture conditions with carnitine are useful for future research efforts to identify factor and culture conditions that enhance cardiac cell survival and proliferation (see e.g. page 938-939). Further, Xu teaches that defined albumin-free medium with carnitine is highly desirable in avoiding serum lot to lot variations in their ability to induce differentiation and maintain cell growth (see page 938). Furthermore, in regard to the amount of carnitine taught by Zimmerman, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
Applicant argues improper hindsight regarding the combination of the prior art of Mitalipova et al., Parenteau et al., and Zimmermann et al. because the prior art discloses a large number of ingredients and none of the references teach or suggest a lower albumin level of less than 1X10-4 mg/mL (Remarks, page 19).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. As discussed above, In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Zimmermann teaches albumin-free supplement with carnitine and selenium (see e.g. pages 7, 15, 29, claim 9, fig. 9). Contrary to Applicants argument, the supplement of carnitine is a known medium supplement in the art. Therefore, the knowledge is not coming from the applicant’s disclosure but the prior art shows that a person of ordinary skill in the art would have knowledge of carnitine and albumin free media.
In response to Applicants argument regarding the lower albumin level, the MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Even though the prior art of Mitalipova et al., Parenteau et al., and Zimmermann et al. have a large number of ingredient they are not cited for teaching a lower level of albumin. As discussed above, Chen356 is cited for teaching a low-protein medium (i.e. albumin-free) culture medium (p.2, line 31; p.6, lines 3-7 and lines 25-29; p.13, lines 21-24;p. 14 lines 29-31; p.15, lines 6-9), which reads on the less than 1X10^-4 mg/mL of albumin as claimed.
Applicant argues superior cardiac differentiation efficacy and reproducibility of an exemplary substantially albumin-free cell culture medium encompassed with the present claims 37 (Remarks, page 21-22).
In response to applicant argument, the above secondary consideration arguments have been fully considered but deemed unpersuasive. It is acknowledged that the instant specification discloses that the chemically defined medium of S12 medium showed a higher number of cardiomyocytes compared to B27-supplemented medium (Spec. see e.g. para. 5; Fig. 1) and may have shown a higher differentiation efficacy. However, the comparison of superior results is with the B27 medium and not with what the Examiner considers as the closest prior art (i.e. Chen356). Therefore, the superior results regarding cardiac differentiation efficacy and reproducibility are not considered as a relevant comparison to the closes prior art.
Applicant argues that none of the cited art teaches superior cardiac differentiation, including the cited prior art of Zielinski (Remarks, page 21-22) which does not teach a culture medium that possesses the superior cardiac differentiation efficacy and reproducibility (Remarks, page 21-22)
In response to applicant argument, the above secondary consideration arguments have been fully considered but deemed unpersuasive. It is acknowledged that the cited prior art of Zielinski (Remarks, page 21-22) does not teach a culture medium that possesses the superior cardiac differentiation efficacy. However, Zielinski et al. (US20100018352; prior art of record) is cited for evidence that the combinations of multiple antioxidants may exhibit synergistic effects (para. 51). It is noted that the claims do not recite a limitation regarding a culture medium that possesses the superior cardiac differentiation efficacy. However, the claims are directed to a composition and not a method, therefore even if there was a claim limitation to superior cardiac differentiation efficacy it would not be commensurate in scope with the claims, because the claims are directed to a composition and not a method regarding cardiac differentiation efficacy (e.g. this claim limitation would not change the structure of the composition). Furthermore, the prior art of Wang, as stated supra, discloses that Insulin-transferrin-selenium (ITS) was found to improve the efficiency the reprograming of fibroblast into cardiomyocytes through a pluripotent state (see e.g. para. 23 and page 9-13, 18, claim 16). Thus, the cited art of Chen356, in view of Wang et al., Wang, Xiaowen, et al., Burridge, Paul W., et al., Mitalipova et al., Huang, Peng, et al., Zimmermann et al., Xu et al., Duanqing Pei et al., and Parenteau et al. would make the claimed cell culture medium (i.e. claim 37 and 131) as obvious, as discussed above. Therefore, it is the examiner’s position that the combined teachings would render the claimed invention obvious.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 9AM - 5:00PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Doug Schultz can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631