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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/13/2025 has been entered.
Response to Amendment
The amendment filed 6/13/2025, amending claim 1 and cancelling claims 10 and 11 is acknowledged. Claims 1, 4, and 9 are pending and under examination. Applicant’s amendments to the claims have overcome the 112(a) rejection, 112(b) rejections, and 103 rejection of claims 1 and 4 as being unpatentable over Grisendi and in further view of Berg, and 103 rejection of claim 9 as being unpatentable over Grisendi and Berg, as applied to claims 1 and 4 above, and in further view of Yuan as previously set forth in the Final Office Action mailed 12/16/2024.
Applicant amended the claims to remove “phenotype” and instead recite “human adipose tissue derived pericytes (AD-PC)”. Grisendi, Berg, and Yuan do not teach adipose-derived pericytes.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1, 4, and 9 and Grisendi and Berg have been considered but are moot because the new ground of rejection does not rely on any reference (Grisendi and Berg) applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Claim Objections
Claim 1 is objected to because of the following informalities:
In line 7, there is no conjunction “and” before terminal ‘wherein’ clause.
Appropriate correction is required.
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, 4, and 9 are 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.
Claim 1 recites a method for the production of cellular particulate with antitumor activity, wherein it comprises isolating the cellular particulate from a supernatant collected from a cell population culture, wherein the cell population is a human adipose tissue derived pericytes (AD-PC), wherein the cells are transfected in a stable manner with a retroviral vector encoding soluble Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), wherein the cells express an antitumor soluble TRAIL.
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).
The claims fail to recite, and the specification fails to disclose, the structure/function nexus between the expression of sTRAIL and the composition of the thus-isolated cellular particulate [structure] having antitumor activity [function].
While it is clear that the claimed method comprises the step(s) of:
i) transducing the AD-PC cell population with a retroviral vector expressing sTRAIL; and
ii) isolating a cellular particulate [structure] having antitumor activity [function] from a supernatant from said AD-PCs,
the claim does not recite/require the thus-isolated supernatant having antitumor activity to comprise the sTRAIL.
The claims encompass some isolation of cellular particulates that do not comprise sTRAIL, yet are to have antitumor activity. Additionally, the claims encompass some other molecule(s) [structure(s)] that, in the absence of sTRAIL, are to achieve the antitumor activity [function].
The specification and working examples do not provide further guidance. For example, Example 2 (pg. 7) compared the levels of TRAIL found in cellular particulate derived from AD-PC-TRAIL cells and AD-PC-EMPTY cells, with no presence of TRAIL in AD-PC-EMPTY derived samples. Example 3 (pgs. 7-8) tested the antitumor capacity of cellular particulate derived from AD-PC-TRAIL cells and AD-PC-EMPTY cells by studying the activity of caspase 8 in A673 cells. “On A673 cells, the mortality induced by the AD-PC-TRAIL derived cellular particulate was 93.1±9.6%, significantly higher than that obtained with AD-PC- EMPTY derived cellular particulate, which instead did not show significant cytotoxicity effects (see fig. 6).” Additionally, “treatment of BXPC3 cells with AD-PC-TRAIL derived cellular particulate gave a mortality of 34.6±3.6%, significantly higher than that obtained with AD-PC- EMPTY derived cellular particulate, which instead did not show relevant cytotoxic effects (see fig. 5).”
As exemplified above, while AD-PC- EMPTY derived cellular particulate did not show significant cytotoxicity effects, the cellular particulate did show some (~15%) in both BXPC3 and A673 cells. Even if minimal, these results would still read upon cellular particulate with antitumor activity, despite not comprising sTRAIL.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
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.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112(b)
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 1, 4, and 9 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.
Claim 1 recites a method for the production of cellular particulate with antitumor activity, wherein it comprises isolating the cellular particulate from a supernatant collected from a cell population culture, wherein the cell population is a human adipose tissue derived pericytes (AD-PC), wherein the cells are transfected in a stable manner with a retroviral vector encoding soluble Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), wherein the cells express an antitumor soluble TRAIL.
It is unclear whether the cellular particulate is required to comprise sTRAIL in order to achieve antitumor activity. As written, the claim does not recite/require the thus-isolated supernatant having antitumor activity to comprise the sTRAIL (discussed in 112(a) rejection above). Therefore, does the method produce isolated cellular particulates that do not comprise sTRAIL yet still have antitumor activity? Can other molecule(s) be present that, in the absence of sTRAIL, still have antitumor activity? Or are the produced cellular particulates with antitumor activity required to comprise sTRAIL?
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “transfected” in claim 1, line 6 is used by the claim in reference to viral vectors (including retroviral vectors), while the accepted meaning in the art for “transfect” is generally understood to refer to plasmid vectors. “Transduce” is generally used in the art to refer to viral vectors, including retroviral vectors. The term is indefinite because the specification does not clearly redefine the term.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “said population expressing TRAIL is selected from: autologous cells, allogenic cells, human cells, and animal cells”, while claim 1, which claim 4 depends upon, also recites “wherein the cell population is a human adipose tissue derived pericytes (AD-PC)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. It is natural law of biology that animal cells (broad) includes human cells (narrow).
Additionally in claim 4, the AD-PCs are autologous vs allogenic relative to which human? The reference human, from which to ascertain autologous vs allogenic, is an arbitrary and subjective determination, rendering the claim indefinite. As written, it is unclear how one may determine whether the AD-PCs are autologous or allogenic. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Claim 9 requires the step of isolating a cellular particulate [structure] having antitumor activity [function].
While it is clear that claim 9 requires the step(s) of:
i) centrifuging the isolated cellular particulate of claim 1 [initial centrifugation];
ii) filtering the supernatant of said initial centrifugation; and
iii) further centrifuging said filtered supernatant,
the claim does not positively recite which fraction of the further centrifuged filtered supernatant contains the cellular particulate [structure] having antitumor activity [function].
Is this the cellular particulate pellet? Or, the supernatant of said filtered supernatant post-second centrifugation?
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 requires the AD-PCs to be human cells (i.e., “the cell population is a human adipose tissue derived pericytes (AD-PC)”). Thus, the recitation of “human cells” in claim 4 fails to further limit claim 1.
Additionally, it is natural law of biology that there are only two types of human cells: autologous and allogenic. Recitation of both type in claim 4 fails to further limit the human AD-PCs recited in claim 1.
Further, the recitation of “animal cells” in claim 4 is broader in scope than “human”, as recited in claim 1. Therefore, the recitation of “said population expressing TRAIL is selected from: autologous cells, allogenic cells, human cells, and animal cells” in claim 4 fails to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1 and 4 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Dominici (US20150320803A1, published 11/12/2015).
Regarding claim 1, Dominici discloses a method for the production of cellular particulate with antitumor activity [0041], wherein it comprises isolating the cellular particulate from a supernatant collected from a cell population culture [0096, 0099, 0100], wherein the cell population is a human adipose tissue derived pericytes (AD-PC), wherein the cells are transfected in a stable manner with a retroviral vector encoding soluble Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), wherein the cells express an antitumor soluble TRAIL [0102] (Abstract).
Regarding claim 4, Dominici discloses the AD-PCs being autologous, allogeneic, human or animal cells (claim 4).
Claim Rejections - 35 USC § 103 – New, necessitated by amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Dominici, as applied to claims 1 and 4 above, and in further view of Yuan (Yuan, Z., Kolluri, K. K., Gowers, K. H., & Janes, S. M. (2017). TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. Journal of extracellular vesicles, 6(1), 1265291.).
Regarding claims 9, Dominici teaches the supernatant of ΔTRAIL-expressing AD-PC cells and the AD-PC infected by the empty vector being assayed according to the protocol for the Quantikine Human TRAIL/TNFSF10 kit (R&D Systems, France) [0100]. The protocol for this assay is silent on the specifics on centrifugation and filtration used (attached as NPL).
Yuan teaches transducing MSCs with lentiviruses comprising full-length TRAIL, resulting in the transduced cell population releasing extracellular vesicles (EVs), which are lipid membrane-enclosed nanoparticles of 50-70 nm in diameter released by cells (i.e., cellular particulate) (Abstract). TRAIL-expressing MSCs were cultured in a medium. The cell culture medium was then collected and centrifuged to remove cells and debris. The resulting medium (i.e., supernatant) was then vacuum-filtered to remove large vesicles, and finally ultracentrifuged, resulting in isolated EVs (pg. 2, Methods and Materials, “Isolation of EVs”).
Yuan teaches centrifuging the isolated cell particulate (i.e., EVs) for 10 min at 300xg and then again at 2000xg at 4 degrees Celsius, followed by vacuum filtering the medium through 0.22 micrometer filters (i.e., filtering by gravity), followed by ultracentrifuging for 2 hours at 100,000xg at 4° Celsius (pg. 2, “Isolation of EVs”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to combine the method of isolating cellular particulate from supernatant taught by Yuan with the method for the production of cellular particulate with antitumor activity taught by Dominici to arrive at the claimed invention. One would have a reasonable degree for success for the combination of Dominici and Yuan because both Yuan and Dominici teach methods of transducing and culturing cells with retroviruses and both Yuan and Dominici teach collecting supernatant and isolating cellular particulate from supernatant.
Further, it is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http:www.uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
No claims are allowed.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638