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 .
This is in response to the papers filed July 08, 2025.
Claims 1, 28 and 195 are currently pending in the application. Claim 1 is independent. Claim 1 is amended, claim 195 is newly added, and no claims have been canceled as set forth in the claim set filed 07/08/2025.
Claim 28 is withdrawn from consideration as being drawn to a nonelected invention and species as in the reply filed 01/13/2021.
Claims 1 and 195 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2017/22534, filed March 15, 2017.
Applicant’s claim for the benefit of a prior-filed parent provisional applications 62/309,140, filed 03/16/2016, and 62/308,324 filed 03/16/2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is March 16, 2016.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
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.
Claim 1 remains rejected and claim 195 is newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 07/08/2025.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,' to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Claim 1 recites wherein a method of producing an expanded population of hematopoietic stem cells ex vivo, said method comprising contacting a population of hematopoietic stem cells with:
Pomalidomide,
one or more compounds selected from UM171 and structural analogs thereof,
A-83-01
And where these 3 components are present in amounts that are sufficient to produce an expanded population of human HSCs for at least 12 days.
New claim 195 is limited to contacting the population of human hematopoietic stem cells ex vivo with 3 compounds: the TGFbeta inhibitor A83-01, UM171 and Pomalidomide. Claim 195 as written are broadly directed to a genus of concentrations sufficient to produce an expanded population of human hematopoietic stem cells for at least 12 days.
There is not structure/ function correlation for the claimed genus of structural analogs of UM171 and amounts of each: pomalidomide, UM171 and A-83-01 able to expand hematopoietic stem cells ex vivo , e.g, Lin−CD34+CD45RA−CD90+CD49f+EPCR+ HSCs, when cultured for at least 12 days. There is not structure/ function correlation for the genus of concentrations of each A83-01, UM171 and Pomalidomide, wherein the combination of these 3 compounds results in an expanded population of human hematopoietic stem cells for at least 12 days.
First, the limitation of “UM171 and structural analogs thereof” lack adequate written description.
The genus of UM171 and structural analogs thereof is extremely broad.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
The specification discloses UM171 analogs in Table 1 to provide structure, however, only a list of possible functions of UM171 and analogs.
As taught by Fares (2014. Science 345(6203): 1509-1512; previously cited), more than 300 newly synthesized analogs of UM729 were examined, of which one (UM171) as demonstrated in Fig. 1C was 10 to 20 times more potent than UM729, with effective concentrations of 17 to 19 nM when tested for its ability to stimulate the expansion of a HSC-enriched population, CD34 + CD45RA– cells (Fig. 1D) (p. 1510, middle column). Thus, Fares highlights that the chemical structure of the analogs of UM729 such as UM171 and its biological activity in expanding CD34+CD45RA– cells is unpredictable. Furthermore, Fares states ,“UM729 did not expand mouse HSCs though both “UM729 and UM171 treatment enhanced the engraftment potential of CD34+ macaque cells by threefold when compared with controls (p. 1510, middle column), further underscoring species unpredictability between chemical structure of the UM729 and UM171 compounds and their biological activity. Figure 1A-D is provided below to illustrate the results.
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Thus, Fares teaches structural analogs of UM171 such as UM729 (being less active on expanding CD34+CD45RA– mPB cells after 7-day cultures) do not have the same function as UM171.
In the working examples, only UM171 is utilized. No other analogs are present in Example 1, Figure 6, 11, and 13.
Therefore, only UM171 has adequate written description in the claims and specification.
Second, the genus of any amount of the combination of pomalidomide, UM171 and A-83-01 is extremely broad and does not have adequate support in the specification.
The specification does not provide support for any range of concentration.
Paragraph 00960 discloses “small molecules at the following final concentrations (all stock solutions were prepared with DMSO as the solvent): A83-01(1 microM, Tocris), Pomalidomide (2 microM, Selleckchem), UM171 (35 nM, ApexBio). These are the only concentrations utilized in the culture and the only concentrations disclosed.
Additionally, the Appeal Brief filed 12/17/2024 at page 17 states:
“In contrast, in instant Figs. 9, 11, and 15 (Ex. I) it is clear that the three-way combination of "pomalidomide, one or more compounds selected from UM 171 and structural analogs thereof, and A- 83-01" unexpectedly increases the population of hematopoietic stem cells by a striking amount as compared to the results observed when only one or two of these reagents are used. For example, when the use of all 3 reagents in Fig. 11 is compared to the use of only A-83-01, the improvement is 1000x. If compared to the use of pomalidomide or UM171, the improvement is 100x.”
This figure utilizes only A83-01(1 microM), Pomalidomide (2 microM), UM171 (35 nM) and shows results from Example 1.
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Examples 2-7 do not provide alternative concentrations of A83-01, pomalidomide, or UM171 to obtain the claimed results.
Moreover, FIGS. 73A-73B demonstrate the absolute number of Lin−CD34+CD45RA−CD90+CD49f+EPCR+ HSCs after CD34+ bone marrow cells were cultured for 12 Days.
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As taught by Fares (2014) UM171 was 10 to 20 times more potent than UM729, with effective concentrations of 17 to 19 nM when tested for its ability to stimulate the expansion of a HSC-enriched population, CD34 + CD45RA– cells (Fig. 1D). Therefore, Fares teaches a concentration known in the art, however, the concentration of 35 nM in combination with A83-01(1 microM), Pomalidomide (2 microM) would have been unpredictable to achieve unexpected results.
Therefore, use of any concentration of the at least 3 components claimed does not have adequate written description.
Therefore, the breadth of the claimed element concentrations and amounts are absent in Claim 1 and does not match with the necessary working concentrations of the invention and the limited disclosure is not sufficient enough to meet the threshold of adequate written description.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
In response to Applicant’s arguments and amendments regarding the 112 rejections of claim 1,
Applicant’s arguments have been considered, however they are not persuasive.
Applicant argues that nowhere does Fares states both UM171 and UM729 expand human HSCs and points to DMSO control of Figure 1D which is referenced in the above rejection. Applicant further argues that both UM729 and UM171 enhance engraftment potential of CD34+ macaque cells according to p.1510. Therefore, Applicant states that the same type of function in each system where Fares tests both human and macaque. Moreover, Applicant argues Fares only reports UM729 to have no effect in mice HSC and the present claim set has been amended to require human HSCs.
Examiner acknowledges that Fares shows functional similarities between analogs of UM729, however UM171 is a known optimized form of UM729 which is 10 to 20 times more potent (Fig 1 description, p.1510, 2nd column). While the “same type of function” is present, the differences of magnitude of function are great between the different analogs as seen by Fig 1A. Furthermore, UM171 and UM729 require different concentrations to be effective and not cause a cell count less than the DMSO control (Fig 1D), where it is unequivocally clear that the required concentration of UM171 on expansion of CD34+CD45RA– mPB cells after 7-day cultures is less than for UM729. Thus, the concentrations required for expanding a population of human hematopoietic stem cells ex vivo with UM 171 and structural analogs thereof are not the same. Furthermore, the claims are directed to methods of producing an expanded population of human hematopoietic stem cells ex vivo and not to enhance the engraftment potential of CD34+ macaque cells. Thus, applicants’ arguments are not on point.
Applicant argues that their incorporation by reference of structural analogs known to have the same type of function has adequate written description.
Examiner acknowledges that many analogs are noted in the application, however not every variant or even any variant would necessarily produce the same claimed results as there is not adequate written description for any structural analogs of UM171 aside from UM171.
Applicant argues possession of the claimed invention is directed to a “method of producing an expanded population of human HSCs” and not any synergy between components or level of expansion. Therefore, written description is satisfied and demonstrated.
While synergy is mentioned in the arguments as it has been a past subject of secondary considerations, synergy is not stated in the rejection above. Therefore, the arguments against the utilization of synergy is moot and any argument of Official notice is not applicable. Furthermore, the issue of the components is directed towards the “one or more” limitation of UM171 structural components as no Example shows more than one analog, or even an analog other than UM171. Applicant’s arguments for unexpected results can only be met by the claims being in commensurate with the scope of the invention. The invention only has UM171, pomalidomide and A-83-01 at particular concentrations.
Applicant argues that the previous argument of effective concentrations is flawed. Particularly that a broader range of was shown to be effective in expanding HSCs in Figure 1.
Examiner acknowledges that while the range may be broader from 0.01 to about 1, there are particular concentrations within Figure 1 which demonstrate a decrease in cell count which are different for each compound. This suggests that an effective dosage range is necessary to utilize UM171 or 729 which demonstrates that their function is dose dependent. Possession has been demonstrated and Fares has indicated that there are particular ranges effective in utilizing components. There is not sufficient written description for the entire scope of the claims.
Applicants further state that “Table 1 of US 2015/0011543 depicts a large number of structural analogs of UMl 71 and reports their "Biological data (ECso)" which is defined as "the concentration that results in a 50% increase in CD34+CD45RA- cell count compared to vehicle cultures (DMSO)”. However no such limitation exists in the claims as written. Hence the argument is not persuasive as they argue limitations that are not present in the claims.
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.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634