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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 06 November 2024.
CLAIMS UNDER EXAMINATION
Claims 6, 10, 30-32, 38, 40, 45-46 and new claims 47-48 have been examined on their merits.
PRIORITY
A certified translation of the foreign application has not been provided.
WITHDRAWN REJECTIONS
The rejection of claims 6-7, 10, 27-32, 38, 40 and 45-46 under 35 U.S.C. 112(b) are withdrawn due to claim amendment.
The rejection of claims 7 and 27 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are now moot due to claim cancellation.
REJECTIONS
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 6, 10, 30-31, 38, 40 and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Hattori et al. (previously cited; Method For Purifying Cardiomyocytes or Programmed Cardiomyocytes Derived From Stem Cells or Fetuses. US20090275132) in view of Mitcheson et al. (previously cited; Cultured adult cardiac myocytes: Future applications, culture methods, morphological and electrophysiological properties, Cardiovascular Research: 39 (1998) 280-300).
Hattori et al. teach a method of purifying cardiomyocytes from a cell mixture at a high degree of purification ([0017]). Hattori discloses the following at [0018]:
The inventors of the present invention conducted an exhaustive study for the compositions of various kinds of culture medium, in order to construct a system for efficiently producing cardiomyocytes derived from embryonic stem cells. Based on the results regarding a study for a concentration of each components of various culture medium or a study for the timing of changes in a concentration of each components of various culture medium obtained by changing compositions of components of various culture medium, the inventors of the present invention found the following events:
The disclosed method can be used to purify cardiomyocytes from adult stem cells ([0026]). This is interpreted to be a mixture. The art teaches differentiation of embryonic stem cells is “induced” to produce cardiomyocytes ([0052]). As evidenced by the Instant Specification, an embryonic stem cell is a pluripotent stem cell ([0002]). The art teaches the presence of “non-cardiomyocytes” that are selected to undergo cell death ([0019]). The art teaches the non-cardiomyocytes can be derived from embryonic stem cells ([0027]).The art teaches “in the present invention, any cells other than the cardiomyocytes or cells which differentiate into the cardiomyocytes in the future (such as undifferentiated mesoblast cell, the programmed cardiomyocytes) are referred to as a ‘non-cardiomyocyte’” ([0059]). Therefore the embryonic stem cells read on the claim limitation. Therefore the art teaches inducing differentiation from pluripotent stem cells to cardiomyocytes to produce a mixture comprising cardiomyocytes and non-cardiomyocytes as recited in claim 6.
Hattori discloses “events” that can be used to efficiently produce cardiomyocytes ([0018]-[0026]). The art teaches the described selection method is used to select the cells of interest by culturing the cell mixture under the condition to which the cardiomyocytes are physiologically resistant, and therefore, is referred to as “physiologically resistance-based selection method” ([0063]).
Hattori teaches selection of cardiomyocytes by culturing under sugar-free conditions ([0037]). Hattori discloses when the culture medium is deprived of sugar, non-cardiomyocytes undergo cell death ([0071]). Hattori teaches it is effective to supplement the culture medium with a lactic acid (Lactate, 0.1-5 mM) or a pyruvic acid (0.5-5 mM) in place of the sugars ([0071] [0072]). Examiner notes the Instant Specification teaches “by stating that a cell culture medium is supplemented with pyruvate, it is meant that the cell culture medium to be used is supplemented with pyruvate (pyruvic acid)” ([0111]). Therefore the pyruvic acid taught by Hattori reads on pyruvate. It is of note Figure 8 discloses culturing under a sugar-free and lactic acid-supplemented condition for selection of cardiomyocytes.
Hattori teaches the following:
differentiation from pluripotent stem cells to cardiomyocytes;
a mixture of cardiomyocytes and undifferentiated pluripotent stem cells;
culturing under sugar free conditions; and
supplementing with lactic acid or pyruvic acid.
Hattori teaches changing compositions of components of various culture mediums to obtain cardiomyocytes.
The deficiency of Hattori is that it does not explicitly teach culturing in a medium that is also free of glutamine.
Mitcheson teaches a method of culturing cardiomyocytes (see title; Abstract). Mitcheson teaches “the basic, ‘non-supplemented’’ medium routinely used to culture adult heart cells is bicarbonate buffered medium” (page 283, right column, last complete paragraph). Medium 199 “contains all amino acids except glutamine, vitamins, CaCl2, 1.8; NaCl, 116; Na acetate, 0.6; NaHPO , 1; KCl, 5.3; MgSO , 0.8”. Common additional supplements are creatine, taurine, L-carnitine, pyruvate and insulin. (page 283, right column, “Culture Medium” section). Examiner interprets “except glutamine” to mean no glutamine is present. Examiner notes pyruvate reads on a substitute for sugar as taught by Hattori at ([0071][0072]).
In the section titled “Medium changes”, Mitcheson teaches glutamine free conditions do not support cell division, avoiding the problems of contamination of myocyte cultures by rapidly dividing non-myocytes” (page 284, right column, third paragraph). Therefore Mitcheson teaches culturing in cell culture medium that does not contain glutamine to prevent contamination of myocyte culture with dividing non-myocytes.
It would have been obvious to combine the teachings of Hattori and Mitcheson by culturing a mixture of cardiomyocytes and non-cardiomyocytes in a cell culture medium with no glutamine. One would have been motivated to do so since Mitcheson teaches culturing cardiomyocytes in a medium without glutamine. Mitcheson teaches glutamine free conditions do not support cell division, avoiding the problems of contamination of myocyte cultures by non-myocytes. One would have had a reasonable expectation of success since Mitcheson teaches cardiomyocytes can be cultured without glutamine. One would have expected similar results since both references are directed to cardiomyocyte cultures. Because culturing in a medium without glutamine is rendered obvious, it would be expected to induce cell death of undifferentiated stem cells.
It would have been obvious to culture in a media that also contains pyruvate but that is void of sugar. One would have been motivated to do so since Hattori teaches these conditions can be used to purify cardiomyocytes from stem cells. One would have had a reasonable expectation of success since Hattori teaches these conditions can successfully be used to select for cardiomyocytes, and Mitcheson teaches cardiomyocytes can be cultured in a media containing pyruvate without sugar. Claim 6 is rendered obvious.
Hattori teaches cells can be selected for 24 hours under a low serum condition ([0078]). Therefore claim 10 is included in this rejection.
Hattori discloses when the culture medium is deprived of sugar, non-cardiomyocytes undergo cell death. Hattori studied an alternative substrate which can preferentially provide the cardiomyocytes with an energy other than sugar. Hattori teaches it is effective to supplement the culture medium with a lactic acid (Lactate, 0.1-5 mM) or a pyruvic acid (0.5-5 mM) ([0071] [0072]). Therefore Hattori teaches lactate supplemented medium. Claim 30 is included in this rejection.
Hattori teaches pyruvate supplemented medium ([0072]). Therefore claim 31 is included in this rejection.
Hattori teaches the use of human embryonic stem cells (see [0053]). Therefore claim 38 is included in this rejection.
As set forth in the rejection of claim 6 above, Hattori discloses culturing under sugar free conditions. Hattori identifies glucose as a sugar ([0064]). Claim 40 is included in this rejection.
Regarding independent claim 45: The teachings of the prior art are reiterated. Hattori teaches selection of cardiomyocytes by culturing under sugar-free conditions ([0037]).
While Hattori teaches culturing in a culture medium that is sugar free, the art does not teach culturing in a medium that is also free of glutamine.
The teachings of Mitcheson are reiterated.
It would have been obvious to combine the teachings of Hattori and Mitcheson by culturing a mixture of cardiomyocytes and non-cardiomyocytes in a cell culture medium with no glutamine. One would have been motivated to do so since Mitcheson teaches culturing cardiomyocytes in a medium without glutamine. Mitcheson teaches glutamine free conditions do not support cell division, avoiding the problems of contamination of myocyte cultures by non-myocytes. One would have had a reasonable expectation of success since Mitcheson teaches cardiomyocytes can be cultured without glutamine. One would have expected similar results since both references are directed to cardiomyocyte cultures. Because culturing in a medium without glutamine is rendered obvious, it would be expected to induce cell death of undifferentiated stem cells.
It would have been obvious to culture in a media that also contains pyruvate but that is void of sugar. One would have been motivated to do so since Hattori teaches these conditions can be used to purify cardiomyocytes from stem cells. One would have had a reasonable expectation of success since Hattori teaches these conditions can successfully be used to select for cardiomyocytes, and Mitcheson teaches cardiomyocytes can be cultured in a media containing pyruvate without sugar. Claim 45 is rendered obvious.
Hattori teaches selection of cardiomyocytes by culturing under sugar-free conditions ([0037]). Sugar free conditions read on the amount of sugar recited in claim 46.
Hattori teaches induced pluripotent stem cells can be used ([0059]). Therefore claim 47 is included in this rejection.
Hattori teaches embryonic stem cells (supra). Therefore claim 48 is included in this rejection.
Therefore Applicant’s invention is rendered obvious as claimed.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Hattori et al. in view of Mitcheson as applied to claim 6 above, and further in view of Whitford et al. (previously cited; Lipids in Cell Culture Media. 2008 Pages 152-154).
Claim 6 is rejected as recited in the rejection above.
While Hattori teaches the use of sugar-free culture media, the art is silent regarding the presence of fatty acids in said media. The teachings of Mitcheson have been set forth above.
Whitford teaches supplementing cell culture systems with particular fatty acids “significantly improves performance” (page 152, middle column).
It would have been obvious to supplement the culture media disclosed by Hattori with fatty acids. One would have been motivated to do so since Whitford teaches particular fatty acids can be used in cell culture systems. One would do so to improve cell culture performance, as taught by Whitford. One would have had a reasonable expectation of success since Whitford teaches fatty acids can be added to cell culture media. One would have expected similar results since both references are directed to cell culture. Therefore claim 32 is included in this rejection as claimed.
Therefore Applicant’s Invention is rendered obvious as claimed.
37 CFR 1.132 Declaration
The examiner acknowledges receipt of the Declaration under 37 CFR 1.132 by Dr. Keiichi Fukuda filed on 06 November 2024.
The Declaration notes Mitcheson teaches the following at section 2.2.3 (page 283, right column, last complete paragraph):
The basic, “non-supplemented” medium routinely used to culture adult heart cells is bicarbonate buffered Medium 199 (e.g. Refs. [24,37,48]). Medium 199 “contains all amino acids except glutamine, vitamins, CaCl2, 1.8; NaCl, 116; Na acetate, 0.6; NaHPO , 1; KCl, 5.3; MgSO , 0.8”.
The Declarant argues this means the medium in reference 24 (Ellingsen et al.) is used. The Declaration states scientists who have ordinary skill and knowledge in cell culture would conclude that Mitcheson’s medium includes sugar. The Declarant states “I could not see another possibility”. The Declaration states it would be unscientific if Mitcheson’s experiments used a medium that does not include sugar since such a medium would not allow myocytes to survive. The Declaration states this would be useless and nonsensical.
Regarding Ellingsen (cited as an example by Mitcheson): the Declaration acknowledges Ellingsen teaches the medium does not contain glutamine. The Declaration acknowledges Ellingsen does not teach the presence of sugar. The Declaration argues it is customary in the field that the product catalog would only list what is added to a base medium. Therefore the Declaration alleges the medium must contain sugar since base mediums with sugar are known. The Declaration provides the product description from a different medium (M7528) and notes that it contains glucose. Therefore the Declaration states Mitcheson’s medium must also contain sugar.
The Declaration under 37 CFR 1.132 filed 06 November 2024 is insufficient to overcome the rejection of claim 6 based upon obviousness over Hattori in view of Mitcheson et al. as set forth in the last Office action because:
Mitcheson teaches “the basic, non-supplemented medium routinely used to culture adult heart cells is bicarbonate buffered Medium 199 (e.g. Refs. [24,37,48]). Medium 199 “contains all amino acids except glutamine, vitamins, CaCl2, 1.8; NaCl, 116; Na acetate, 0.6; NaHPO , 1; KCl, 5.3; MgSO , 0.8”.
It is well known that the term “e.g.” means “for example”. Therefore references 24, 37 and 48 are exemplary. Mitcheson does not teach the formulations taught in the exemplary references are used in the disclosure. Mitcheson does not teach the formulations taught by Ellingsen are used. As acknowledged in the Declaration, Ellingsen does not teach a medium containing sugar.
While the Declaration argues Medium 199 must contain sugar, Sigma Aldrich (discloses “Medium 199 is available in several different formulations” (see first two lines of page 2). This reference was cited as evidentiary art in the Office action mailed on 06 May 2024. Therefore the term “Medium 199” does not define a specific set of chemical components. As evidenced by US Biological Life Sciences (previously cited as art of record) Medium 199 can also be formulated without glucose or glutamine (see ingredient list). As disclosed by MyBiosource (art of record), “Medium 199” containing glutamine can be prepared “without glucose” (see product name). Therefore “Medium 199” is not required to contain sugar (e.g. sugar), as alleged by the Declaration. Examiner reiterates Mitcheson does not teach Medium 199 containing sugar or glucose. The ingredient list taught by Mitcheson does not include glucose. The Declaration has provided arguments disclosing various formulations that contain sugar, but has not provided evidence that Mitcheson uses a medium that requires sugar.
The Declaration states it would be unscientific if Mitcheson’s experiments used a medium that does not include sugar since such a medium would not allow myocytes to survive. In response, Examiner notes Hattori teaches a culture medium that is “deprived of sugar” to induce cell death in non-cardiomyocytes (supra). Hattori teaches “it is effective to supplement the culture medium with a lactic acid (Lactate, 0.1-5 mM) or a pyruvic acid (0.5-5 mM) in place of the sugars (supra). Therefore one would have had a reasonable expectation of success using a culture medium that excludes sugar.
The rejection made above is not based on incorporating the entirety of Mitcheson’s medium in Hattori’s method. The rejection cites why it would have been obvious to exclude glutamine in the medium taught by Hattori. Hattori teaches changing compositions of components of various mediums to construct a system that selects for cardiomyocytes. Hattori explicitly excludes sugar and teaches sugar substitutes (lactic acid, pyruvic acid) “can specifically provide the cardiomyocytes with necessary nutrients” ([0072]). Hattori is silent regarding the presence of the amino acid glutamine. Mitcheson explicitly teaches excluding this amino acid in culture mediums to select for cardiomyocytes. Therefore the arguments presented in the Declaration are not persuasive.
Affidavits or declarations are provided as evidence and must set forth facts, not merely conclusions. In re Pike and Morris, 84 USPQ 235 (CCPA 1949).
Upon consideration of the facts taught by the prior art and the information submitted by the Affiant, the balance of evidence indicates that the prior art teaches the instantly claimed inventions.
APPLICANT’S ARGUMENTS
The arguments made by Applicant in the response filed on 06 November 2024 are acknowledged. The Applicant argues Hattori’s sugar-free medium is made for research, while Mitcheson describes experiments for primary culture. The Applicant alleges Mitcheson’s medium includes sugar and nutrients that allow the cells to thrive. The arguments state Mitcheson use the medium disclosed in reference 24 (Ellingsen et al).
The Applicant argues the M199 medium taught by Mitcheson contains glucose. The Applicant argues Hattori teaches sugar-free culture media. Therefore the Applicant argues one would not have combined the teachings of Mitcheson and Hattori. The arguments reiterate the statements made in the Declaration filed on 06 November 2024.
EXAMINER’S RESPONSE
The arguments are not persuasive. The Applicant argues Hattori’s sugar-free medium is made for research, while Mitcheson describes experiments for primary culture. In response: Examiner reiterates that both references teach mediums used that are used to culture and select cardiomyocytes. Therefore this argument is not persuasive.
The Applicant argues sugar, which is not taught by Mitcheson, is necessarily present in Mitcheson’s medium. In response, Examiner reiterates Mitcheson does not teach the disclosed Medium 199 contains sugar or glucose. Mitcheson teaches the following:
The basic, “non-supplemented” medium routinely used to culture adult heart cells is bicarbonate buffered Medium 199 (e.g. Refs. [24,37,48]). Medium 199 “contains all amino acids except glutamine, vitamins, CaCl2, 1.8; NaCl, 116; Na acetate, 0.6; NaHPO , 1; KCl, 5.3; MgSO , 0.8”.
It is well known that the term “e.g.” means “for example”. Therefore references 24, 37 and 48 are exemplary. Mitcheson does not teach the formulations taught in the exemplary references is used in the disclosure. While the Applicant argues Ellingsen (cited as reference 24 by Mitcheson) teaches a medium containing sugar, Mitcheson does not teach Ellingson’s media is used in the disclosed method.
Hattori teaches changing compositions of components of various mediums to construct a system that selects for cardiomyocytes. Hattori explicitly teaches excluding sugar and teaches the sugar substitutes (lactic acid, pyruvic acid) “can specifically provide the cardiomyocytes with necessary nutrients” ([0072). Hattori is silent regarding the presence of glutamine. The rejection is not based on incorporating Mitcheson’s medium in Hattori’s method. The rejection cites why it would have been obvious to exclude glutamine in the medium taught by Hattori. Mitcheson teaches excluding glutamine in culture mediums to select for cardiomyocytes. One would have been motivated to do so since Mitcheson teaches culturing cardiomyocytes in a medium without glutamine. Mitcheson teaches glutamine free conditions do not support cell division, avoiding the problems of contamination of myocyte cultures by non-myocytes. One would have had a reasonable expectation of success since Mitcheson teaches cardiomyocytes can be cultured without glutamine. Therefore the arguments are not persuasive.
ART OF EVIDENCE
Millipore Sigma. Medium 199.
US Biological Life Sciences. Medium 199 w/ Earle’s w/o Amino Acids, Glucose (Powder, TC 199).
MyBiosource. Medium 199 w/Earle’s, L-Glutamine, w/o Glucose Culture Media.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the APIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
Prosecution Insights