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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/13/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6,8-9,12,14,47-48,57,60,63 and 66 in the reply filed on 06/27/24 is acknowledged.
Claims 34-36,39,42, and 68 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/27/2024.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1,2,12,14,47 and 66 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The invention relates to a culture medium for, and method of, preferentially expanding the long-term CD34+CD90+CD45RA- subpopulation of cells in a culture of hematopoietic stem cells (HSCs) while CD34+ cells are still expanded to a lesser degree. The claims have been amended to recite this enrichment along with the addition of a ratio of HAT and HDAC inhibitors to be added. As set forth above, the term “enriched” is not clear. For the purposes of this rejection, the claims will be considered in terms of favoring the CD34+CD90+CD45RA- cells over any other cells in the culture.
The Specification and art at the time of filing teach that HAT and HDAC are opposing activities with HAT acetylating histones and HDAC deacetylating histones. Peserico (Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology Volume 2011, Article ID 371832, 10 pages) taught that there are 18 different human HDACs, classified into 4 classes and two groups of HATs with the HAT A family being further divided into 3 subclasses. Peserico discusses that the balance between acetyltransferases and deacetylases provides a major contribution to the regulation of cellular functions and the loss in equilibrium between the two activities is associated with disease states. An acetylation balance shifted towards deacetylation is required for maintenance of an undifferentiated state while the opposite occurs during lineage progression (differentiation). Peserico teaches that interaction between HATs and HDACs is dynamic and is consistent with the use of epigenetic modulators during cell reprogramming. Olzscha (Sibaji Sarkar (ed.), Histone Deacetylases: Methods and Protocols, Methods in Molecular Biology, vol. 1436, DOI 10.1007/978-1-4939-3667-0_19, © Springer Science+Business Media New York 2016, Chapter 19, page 281-303) also teaches the various classes of HDACs and HDAC inhibitors (HDIs). The different inhibitors inhibit different classes of HDACs with different specificities. Thus, different inhibitors will have different effects and would be used at different concentrations to achieve desired results.
Notably, in Applicant’s Remarks dated 03/05/2025, Applicant provides arguments of the nonobviousness of the now recited ratios of HDAC:HAT inhibitor to achieve CD34+CD90+CD45RA- cell enrichment. Applicant asserts that the claimed ratios are not a matter of routine optimization and that one of ordinary skill would need to derive various sets of different compound combinations and test their effectiveness to arrive at the solution of combining HAT and HDAC inhibitors at the particularly recited ratio and concentration (see Remarks, 8).
The claims require enrichment of the CD34+CD90+CD45RA- subpopulation of cells in the growth medium. To favor a certain subpopulation, the skilled artisan looks to the Specification for guidance as to what culture media supports the enrichment of this subpopulation. Paragraph 157 refers to a basal medium used at 1X with a supplement that is stored at 50X. Paragraph 158 states, “All media were supplemented with 100 ng/mL SCF, 100 ng/mL FLT-3L, 100 ng/mL TPO, 50 ng/mL IL-3, and 20 ng/mL IL-6 (all provided by Thermo Fisher Scientific).” Paragraph 170 states, “HSC Medium (HSC Basal and 50X Supplement) or three commercial media, all supplemented with growth factors (SCF, FIt3L, TPO, IL-3, and IL-6).”
Paragraph 158 discusses use of a variety of media to compare HSC expansion, including HSC Medium (as provided herein), and the commercially available Stem Cell Growth Medium (SCGM, CellGenix GmbH), STEMSPAN™ Animal Component Free (ACF, STEMCELL Technologies), and STEMPRO™ 34 (Thermo Fisher Scientific).” The specification does not clearly establish what “HSC Medium (as provided herein)” is. The claimed supplement is presumed to be STEMPROTM HSC Supplement (50X). Figure 7 shows that the CD34+CD90+CD45RA- subpopulation of cells is highly favored by the HSC Medium compared to 3 competitor media. The Specification refers to HASC Medium as HSC Basal and 50X Supplement (para 36) but does not teach its composition.
The Specification addresses addition of HDAC and HAT inhibitors in Example 2 and finds their effect to be synergistic in that removal of 1 inhibitor results in a lower yield than removal of both. The inhibitors used are VPA (HDAC inhibitor) and garcinol (HAT inhibitor) and they were added to each of the competitor media “at the final concentration present in HSC Medium”. This final concentration is not disclosed but is a critical feature of the invention (see above). Table 1 shows Garcinol and VPA greatly enhanced CD34+CD90+ when added to HSC Medium and this effect was less for SCGM and no data is shown for ACF. Paragraph 164 concludes, “Garcinol and VPA do not work in combination when added to competitor media” and “Garcinol and VPA in combination improved performance across TNC, CD34+, CD34+CD90- populations”.
Given the art accepted complexity of the balance of histone acetylation with HDACs and HATs and their natural inhibitors and Applicant’s own arguments that “There is no reasonable expectation of success in arriving at the combination of HAT inhibitor and HDAC inhibitor, the weight ratio of HAT inhibitor to HDAC inhibitor, or the concentration of each” the specification is not enabling for the full breadth of the claims.
Thus, the Specification is determined to support preferential expansion of a desirable CD34+CD90+ subpopulation in SHSC Basal Medium with 50X Supplement with the HDAC inhibitor, VPA and the HAT inhibitor, garcinol. However, it would require an undue amount of experimentation to determine which combination of culture conditions would preferentially favor the now-recited CD34+CD90- population.
Applicant argues that the claims are now limited to the specific HDAC and HAT inhibitors present at specific concentrations that are supported as being effective by the specification. However, the above-stated issue with the media composition remains. The evidence of record shows that the balance of HDAC/HAT activity have varying effects that are also dependent on the composition of the media. The effective media supported by the specification is “HSC Media”, the composition of which does not appear to be taught. Other commercial media were not effective as supported by the working examples and Figure 7. The rejection stands because only a single media was taught to be effective. Applicant is referred to paragraph 153 of the specification, which states, “The use of a supplement in combination with a basal medium as described herein and referred to herein as “HSC Medium” to expand HSCs results in a higher proportion of CD34+CD90+CD45RA- cells in the expanded cell population….Moreover, the addition of HAT inhibitor and HDAC inhibitor to competitor media did not result in a corresponding increase in the CD34 CD90" CD45RA" subpopulation — indicating that the effect is not due solely to the presence of VPA/Garcinol, but rather to the supplement more generally.”
Applicant is referred to Figure 7E:
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The total lack of enablement is on the basis that the composition of HSC medium does not appear to be disclosed and it also appears to be the only medium of the four used, to obtain the claimed results.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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