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 ACTION
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendments
Applicant’s amendments and response filed Nov. 19, 2025 have been received and entered into the case.
Status of the Claims
Claims 1-20 are currently pending.
Claim 6 is amended.
Claims 1-20 have been considered on the merits.
Specification Objections
Specification objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are maintained and a correction has been made on pg. 6 where the reference referred to should have been Hickman and not Brewer.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-6, 8, and 10-20 are rejected under 35 U.S.C. 103 as being unpatentable over Brewer (US 2008/0160006 A1) (ref. of record) as evidenced by Zeiger et al. (In Vitro Neurotoxicology, 2011) (ref. of record) and in view of Hickman et al. (US 2014/0206028 A1) (ref. of record).
With respect to claim 1 (a)-(c), Brewer teaches a cell medium comprising sodium chloride (NaCl) at 30,000-150,000 µM (30-150 mM), potassium chloride (KCl) at 2500-10000 µM (2.5-10 mM), and calcium chloride (CaCl2) at 0-3000 µM (0-3 mM) (abstract and Table 1).
With respect to claim 1 (d) and claim 4, Brewer teaches the composition comprising a hydrogen ion buffer to maintain the pH in the desired range which can be sodium bicarbonate in the range of 5,000 to 25,000 µM (5-25 mM) (0025). Additionally, with respect to claim 4, Brewer teaches the composition comprising sodium phosphate monobasic in a concentration ranging from 250-4000 µM (0.25-4.0 mM) (Table 1). Brewer teaches the amount added is sufficient to maintain the pH in the desired range of about 6.9 to about 7.7 when in contact with neural tissue (0025).
With respect to claim 1 (e), Brewer teaches the composition comprising additional amino acids including L-arginine hydrochloride (0-2400 µM), L-asparagine-H20 (0-30 µM), L-cysteine (0-60 µM), L-glutamine (0-3000 µM), L-histidine hydrochloride-H2O (0-1400 µM), L-isoleucine (0-5000 µM), L-leucine (0-5000 µM), L-lysine hydrochloride (0-5000 µM), L-methionine (0-1200 µM), L-phenylalanine (0-2400 µM), L-proline (0-500 µM), L-threonine (0-5000 µM), L-tryptophan (0-500 µM), L-tyrosine (0-2400 µM) and L-valine (0-5000 µM) in varying ranges with the outer ranges being 0-5000 µM (Table 1).
With respect to claim 1 (f) and claim 5, Brewer teaches vitamin B12 (cobalamin) (0-1.2 mM), and riboflavin (0-6 mM) (Table 1). Brewer does not teach that the vitamin B12 is cyanocobalamin as recited in claim 1, however one of ordinary skill in the art would readily recognize that cyanocobalamin is a form of vitamin B12.
With respect to claim 1 (g), Brewer teaches the composition comprising glucose 2500-50,000 µM (2.5-50 mM) and sodium pyruvate at 20-500 µM (0.02-0.5 mM) (Table 1).
With respect to claim 1, Brewer teaches the composition with an osmolarity of 200-270 mOsm (0011). Brewer does not teach the range for osmolarity recited in claim 1 of 280 to 340 mOsm/L.
However, Hickman teaches a similar media for neurons (0010, 0033 and Fig. 1). Hickman teaches that “the osmolarity of the media was adjusted to match the osmolarity of adult rat cerebrospinal fluid” which is 295-305 mOsm (0062). Hickman teaches that “each type of medium was formulated to specifically meet the challenges present during each stage of the cell culture process, allowing for significantly improved survival, regeneration, and long-term growth” (0062). In addition, Hickman teaches that the components of their Plating medium, specifically growth factors, anti-oxidants and Neurobasal-A with adjusted osmolarity were essential for the recovery and regeneration of primary hippocampal neurons in culture (0059).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the cell medium taught by Brewer to have an osmolarity of 295-305 mOsm for the benefit of matching the osmolarity of media to that of cerebrospinal fluid and/or to improve the culturing conditions for the particular neuron as taught by Hickman. It would have been obvious to one of ordinary skill in the art to modify the cell culture medium for neurons of Brewer so that the osmolarity of medium was close to physiological levels which is around 295 to 305 mOsm and to adjust the osmolarity within the range of 280-340 mOsm as claimed, since Hickman teaches a cell culture medium with a osmolarity of 295 to 305 mOsm and teaches adjusting the osmolarity depending on the cells and condition of the cells. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the media taught by Brewer, since similar cell culture media for neurons was known to have an osmolarity within the claimed range and was successful at culturing neurons as taught by Hickman. In addition, optimizing the osmolarity for culturing neurons was known as taught by Hickman.
With respect to claims 10-13, Brewer does not teach the cell medium containing cholesterol, cupric sulphate, ferric sulfate or magnesium sulfate (see entire disclosure). Therefore, one of ordinary skill in the art would reasonably expect that the composition of Brewer contains less than 15 µg/ml of cholesterol, less than 0.0005 mM of cupric sulphate, less than 0.05 mM of ferric sulfate and less than 0.05 mM of magnesium sulfate.
With respect to claim 14, Brewer teaches the cell medium comprising MgCl2 (0-4000 µM, 0-4 mM) (abstract and Table 1). With respect to claim 15, Brewer teaches the cell medium comprising ferric nitrate, Fe(NO3), at a concentration of 0.1-1.2 µM (0.0001-0.0012 mM) (abstract and Table 1). With respect to claim 16, Brewer teaches the cell medium comprising zinc sulfate, ZnSO4, at a concentration of 0.2-2 µM (0.0002-0.002 mM) (abstract and Table 1). With respect to claim 17, Brewer teaches the cell medium comprising glycine at a concentration of 0-2400 µM (0-2.4 mM) (abstract and Table 1). With respect to claim 18, Brewer teaches the cell medium comprising L-alanine at a concentration of 0-120 µM (0-0.12 mM) (abstract and Table 1). With respect to claim 19, Brewer teaches the cell medium comprising L-serine at a concentration of 0-2400 µM (0-2.4 mM) (abstract and Table 1).
Although Brewer does not teach the exact ranges recited in claims 1, 4, 5, and 10-19 for the various components, the ranges of the components overlap significantly with the ranges taught. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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) -MPEP § 2144.05. Furthermore, one of ordinary skill would recognize that all of the components of a culture medium are result effective variables and that the concentration of the components of a cell medium would be matter of routine optimization as evidenced by Brewer. Brewer teaches that media are formulated to optimize particular desired cell culture outcomes such improved survival (0004).
With respect to the limitations that the components are present at a concentration that maintains the survival and in vivo-like neurophysiological function of a neural cell cultured in medium in vitro and that the in vivo-like neurophysiological function comprises synaptic function, action potential generation, and/or energetic maintenance in claim 1, these properties would be inherent to compositions with the claimed amounts of components. Accordingly, since the combined teachings of Brewer and Hickman teaches the composition with concentrations within the claimed range, these properties are inherent to compositions taught by Brewer and Hickman. Support for this can be found in the cited references. Brewer teaches the composition promotes the survival and regeneration of adult human neurons grown in culture for weeks and long enough for the appearance of synaptic elements (maintains the survival and neural functionality of neural cells) (0032). Brewer further teaches the composition improves the cell viability of isolated neural cells and nervous system tissue in culture which indicates improved metabolic activity or energetic maintenance (0002 and 0012). Cell viability is used as a measurement of the metabolic activity (energetic maintenance) of the neurons as evidenced by Zeiger. Zeiger teaches to access the metabolic activity of primary neuronal culture and neural cell lines they used a variety of methods including viability assays (abstract). In summary, the composition of Brewer improves the in vivo-like neurophysiological function of energetic maintenance. Brewer does not test the composition for its effects on synaptic function or action potential generation, however, these properties should be inherent to the composition taught by Brewer, since Brewer teaches compositions with concentrations within the claimed range. Additionally, Hickman teaches the neurons in their media are electrically active which would mean that the neurons have synaptic function and action potential generation (0010-0012). Therefore, the combined teachings of Brewer and Hickman teach a cell medium with the claimed characteristics.
With respect to claim 6, Brewer teaches the composition comprising a supplemental agent including the organic chemical compounds of a protein (human albumin), essential fatty acid (lipids), and monosaccharide (glucose) (Table 1 and 0029). With respect to claim 8, Brewer teaches the composition not comprising serum (0011). With respect to claim 20, Brewer teaches the composition comprising a supplemental agent including a protein which is a neurotrophic factor (basic fibroblast growth factor) (Table 1 and 0029).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Claims 2, 3, 7 and 9 are rejected under 35 U.S.C. 103(a) as being unpatentable over Brewer as evidenced by Zeiger and in view of Hickman (as applied to claims 1, 4-6, 8, and 10-20 above), and further in view of Espinosa de los Monteros et al. (US 2012/0052577 A1) (ref. of record) and Kido (US 2012/0177614 A1) (ref. of record).
The teachings of Brewer and Hickman can be found in the previous rejection above.
Brewer does not teach the composition comprising L-aspartic acid at a concentration of up to 0.004 mM as recited in claim 2. However, Espinosa de los Monteros teaches a similar cell medium for neural stem cells comprising NaCl, a neuroactive inorganic salt, glycine, L-alanine and L-serine (0009 and Table 4) which further comprises L-aspartic acid at a concentration of 0.025 mM (Table 4). In further support, Kido teaches a medium for neural stem cells and/or neural progenitor cells comprising various components to support cell health and survival including 100 µM (0.100 mM) of L-aspartic acid (0098). It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit, as disclosed by the cited references above, since each is well known in the art for their claimed purpose as supplements in neural cell culture media and for the following reasons. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients. The idea for combining them flows logically from their having been used individually in the prior art.
Brewer does not teach the composition comprising L-glutamic acid at a concentration of up to 0.04 mM as recited in claim 3. However, Espinosa de los Monteros teaches a similar cell medium for neural stem cells comprising NaCl, a neuroactive inorganic salt, glycine, L-alanine and L-serine (0009 and Table 4) which further comprises L-glutamic acid at a concentration of 0.025 mM (Table 4). In further support, Kido teaches a medium for neural stem cells and/or neural progenitor cells comprising various components to support cell health and survival including 100 µM of L-glutamic acid (0098). It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit, as disclosed by the cited references above, since each is well known in the art for their claimed purpose as supplements in neural cell culture media and for the following reasons. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients. The idea for combining them flows logically from their having been used individually in the prior art.
Brewer does not teach the light sensitive agent is HEPES at a concentration of 0.1-30 mM as recited in claim 7 or at a concentration of 1-10 mM as recited in claim 9. However, Espinosa de los Monteros teaches a similar cell medium for neural stem cells comprising NaCl, a neuroactive inorganic salt, glycine, L-alanine and L-serine (0009 and Table 4) which further comprises HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) at a concentration of 3.75 mM (Table 4). In further support, Kido teaches a medium for neural stem cells and/or neural progenitor cells comprising various components to support cell health and survival including 15 mM HEPES (0098). It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit, as disclosed by the cited references above, since each is well known in the art for their claimed purpose as supplements in neural cell culture media and for the following reasons. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients. The idea for combining them flows logically from their having been used individually in the prior art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing of the invention was made, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Nov. 19, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that one of skill in the art would not have been motivated to modify the media described in Brewer to arrive at the currently claimed range when Brewer is viewed in its entirety and in light of the state of the art at the time (Remarks pg. 6 para. 1-2). However, this argument was not found to be persuasive, since it would have been obvious to optimize the osmolarity of the cell culture medium taught by Brewer depending on the neurons and stage of the cell culture process as taught by Hickman.
Applicant argues that Examiner appears to have conflated disclosures asserted to be present in Brewer has though they were present in Hickman and Brewer does not teach a range of osmolarity of 295-305 mOsm but instead a range of 200-270 mOsm (Remarks pg. 6 para. 3). However, this argument was not found to be persuasive, since the Examiner did not intend to state Brewer teaches a range of osmolarity of 295-305 mOsm and meant for the reference referred to be Hickman and not Brewer. This was a clear mistake, since the paragraphs explaining what each reference teaches do not state that Brewer teaches this limitation or this range of osmolarity and instead it is stated that “Brewer does not teach the range for osmolarity recited in claim 1 of 280 to 340 mOsm/L”.
Applicant argues that Brewer teaches a lower range of 200-240 mOSm is preferred and is intentional in order to decrease the growth of glial cells (Remarks pg. 7 para. 1). However, this argument was not found to be persuasive, since this reasoning is not given in Brewer for the lower range of osmolarity. Indeed, Brewer reports that “Neurobasal™ has less NaCl and less NaHCO3, resulting in a lower osmolarity, and lesser amounts of cysteine and glutamine, resulting in diminished glial growth” (0004). However, Brewer does not state that this is why the osmolarity of their culture medium is in the range of 200-270 or that it is to prevent growth of glial cells. Furthermore, a preferred embodiment does not constitute a teaching way from a nonpreferred embodiment (MPEP 2123).
Applicant argues that based on the disclosure of Brewer one could not consider optimizing osmolarity or increasing it (Remarks pg. 7 para. 1). However, this argument was not found to the persuasive, since the motivation for optimizing or increasing the osmolarity is found in Hickman. Hickman teaches a cell medium for neurons where the osmolarity is adjusted to match that of the cerebrospinal fluid and to the particular neurons in culture so that survival, regeneration and long-term growth are optimized (0062). Specifically, Hickman teaches matching the osmolarity of medium for neurons to that of cerebrospinal fluid which is around 295-305 Osm and further teaches formulating the medium for each stage of the cell culture process (0059 and 0062).
Applicant argues that diminished glial growth would be immediately apparent to one of skill in the art as an advantage, since glial overgrowth was a well-known issue in neuronal cell as evidenced by Lauer which reports one of the challenges of culturing neurons is suppression of glial overgrowth (Remarks pg. 7-8 bridging para.). However, this argument was not found to be persuasive, since Hickman teaches the advantage of having an osmolarity close to cerebral spinal fluid is that the hippocampal neurons are able to recover and regenerate in culture. Furthermore, the claims are to a medium composition and not to a method of culturing neurons without glial cells.
Applicant argues that Brewer clearly articulated a preference for a lower range of osmolarity for the media (Remarks pg. 8 para. 2). However, this was not found to be persuasive, since a preferred embodiment does not constitute a teaching way from a nonpreferred embodiment (MPEP 2123).
Applicant argues Hickman’s teaching of an alternative osmolarity with a distinct cell culture medium is not enough motivation to increase the osmolarity of Brewer’s cell culture media (Remarks pg. 8 para. 3). However, this argument was not found to be persuasive, since Hickman provides additional motivation to modify the medium of Brewer. Hickman teaches matching the osmolarity to rat cerebrospinal fluid which is 295-305 mOsm and formulating teach medium at each stage of the culture process to improve the survival and regeneration of the neurons (0059 and 0062).
Applicant argues that Espinosa de los Monterose and Kido do not remedy the deficiencies of Brewer as evidenced by Zeiger and in view of Hickman and do not disclose the claimed cell culture medium with a osmolarity between 280-340 mOsmL (Remarks pg. 9 para. 2). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Brewer and Hickman were not found to be persuasive as explained above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 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, Peter Paras can be reached on 571-272-4517. 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 PAIR 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.
/EMILY A CORDAS/Primary Examiner, Art Unit 1632