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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 10, 2025 has been entered.
Detailed Action
This action is in response to the papers filed December 10, 2025.
Amendments
Applicant's response and amendments, filed December 10, 2025, is acknowledged. Applicant has cancelled Claims 1-109, amended Claims 111, 116 and 120, withdrawn Claims 114, 117, 119, 122, and 124-128, and added new claims, Claims 131-132
Claims 110-132 are pending.
Election/Restrictions
Applicant has elected with traverse the following species, wherein:
i) the alternative antigen species of the first T cell subpopulation is PRAME, a tumor antigen, as recited in Claim 91;
ii) the alternative antigen species of the second T cell subpopulation is human adenovirus 3 hexon protein, a viral antigen, as recited in Claim 95;
iii) the alternative MSC population is autologous MSC, as recited in Claim 96;
iv) the alternative subject condition is recovering from a cancer that expresses PRAME, as recited in Claims 87, 90-91 and 94; and
v) the alternative additional method step is the subject has or is undergoing a step of immunosuppressive therapy, as recited in Claim 86.
Response to Arguments
Applicant argues that there is no undue burden to search and examine all claims.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant application is a 371, and thus species election requirement is predicated on lack of unity of invention, not search burden.
Claims 110-132 are pending.
Newly submitted Claim 132 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claim is directed to non-elected species, as per Claim 119.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claim 132 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 114, 117, 119, 122, 124-128, and 132 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 110-113, 115-116, 118, 120-121, 123, and 129-131 are under consideration.
Priority
This application is a 371 of PCT/US19/33186 filed on May 20, 2019. Applicant’s claim for the benefit of a prior-filed application provisional application 62/673,756, filed on May 18, 2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed applications 62/673,756, PCT/US2019/33186, and instant specification fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in 62/673,756, PCT/US2019/33186, and instant specification. Thus, 62/673,756, PCT/US2019/33186, and instant specification do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
Applicant argues support for Claim 131 is found in the specification pgs 150-151, which corresponds to [0284] of instant application PG Pub US2021/0213066.
Said paragraph speaks to peptide lengths, not a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy.
Support for a subject having a cancer that expresses PRAME may be found in [0203-204].
While the specification discloses a T cell subpopulation specific for a viral-associated antigen may be directed to e.g. adenovirus (e.g. [0083]), such is in the context of treating HSCT patients with disorders other than malignancies, including HSCT patients susceptible to--not having--a viral infection [0206].
The specification fails to disclose a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy.
Alternatively, if Applicant believes that support for a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy,
is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity by page, and line number or paragraph number, where such support may be found.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
At best, 62/673,756 discloses the peptide library is constituted of peptides that are 15 amino acids in length (e.g. pg 30, line 31).
While [0284] of instant application PG Pub US2021/0213066 discloses the virus-associated antigen peptides for use in activating T cell subpopulations includes peptides that are about 7-16 or more amino acids in length, or 7-35 or more amino acids in length, the specification is silent to the “epitope consists of 8-11 or 13-17 amino acid residues”, let alone HAdV-3 hexon epitopes consisting of 8-11 or 13-17 amino acid residues.
At best, the instant specification discloses HAdV-2 hexon epitopes, to wit, SEQ ID NO’s: 2817-2916 that consist of 8, 9, 10, 11, or 15 amino acids.
PCT/US2019/33186, having the same disclosure as the instant application, suffers the same deficiencies.
Alternatively, if Applicant believes that support for ‘HAdV-3 hexon epitope consists of 8-11 or 13-17 amino acid residues’ is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity by page, and line number or paragraph number, where such support may be found.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
The disclosures of 62/673,756, PCT/US2019/33186, and/or instant specification fail to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the limitations recited in Claim 131 of the instant application.
Accordingly, the effective priority date of Claim 131 is granted as November 18, 2020, the filing date of the instant application.
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.
1. Claim 131 is 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 131 recites a method of treating a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy.
Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, Claim 131 is considered to constitute new matter.
Claim 131 also recites the HAdV-3 epitope consists of 8-11 or 13-17 amino acid residues.
Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, Claim 131 is considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
Applicant argues support for Claim 131 is found in the specification pgs 150-151, which corresponds to [0284] of instant application PG Pub US2021/0213066.
Said paragraph speaks to peptide lengths, not a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy.
Support for a subject having a cancer that expresses PRAME may be found in [0203-204].
While the specification discloses a T cell subpopulation specific for a viral-associated antigen may be directed to e.g. adenovirus (e.g. [0083]), such is in the context of treating HSCT patients with disorders other than malignancies, including HSCT patients susceptible to--not having--a viral infection [0206].
The specification fails to disclose a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy.
Alternatively, if Applicant believes that support for a subject having:
i) a cancer expressing PRAME;
ii) an infection by HAdV-3; and
iii) is undergoing immunosuppressive therapy,
is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity by page, and line number or paragraph number, where such support may be found.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
While [0284] of instant application PG Pub US2021/0213066 discloses the virus-associated antigen peptides for use in activating T cell subpopulations includes peptides that are about 7-16 or more amino acids in length, or 7-35 or more amino acids in length, the specification is silent to the “epitope consists of 8-11 or 13-17 amino acid residues”, let alone HAdV-3 hexon epitopes consisting of 8-11 or 13-17 amino acid residues.
At best, the specification discloses HAdV-2 hexon epitopes, to wit, SEQ ID NO’s: 2817-2916 that consist of 8, 9, 10, 11, or 15 amino acids.
Alternatively, if Applicant believes that support for ‘HAdV-3 hexon epitope consists of 8-11 or 13-17 amino acid residues’ is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity by page, and line number or paragraph number, where such support may be found.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Declarations and new references cannot demonstrate possession of a concept after the fact.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
2. Claim(s) 110-113 and 130 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bollard et al (U.S. 2015/0359876; Applicant’s own work; of record).
With respect to Claims 110 and 130, Bollard et al is considered relevant prior art for having disclosed a method for treating a subject in need of adoptive immunotherapy, the method comprising the step(s) of administering to the subject a cellular composition comprising:
i) a first subpopulation of primed and expanded T cells having specificity for a viral associated antigen;
ii) a second subpopulation of primed and expanded T cells having specificity for a tumor antigen (e.g. [0069], viral antigen and tumor antigen); and
iii) mesenchymal stem cells (e.g. [0082], other cellular products, e.g. mesenchymal stem cells, may be coadministered with the anti-specific T cells according to the invention).
Bollard et al clearly disclosed the T cell composition comprises T cells that recognize a combination of antigens (e.g. [0014] Using Multiple Antigens; [0069], viral antigens in addition to tumor antigens).
With respect to Claims 111-112, Bollard et al disclosed wherein the tumor antigen is PRAME (e.g. [0070]).
With respect to Claims 110 and 113, Bollard et al disclosed wherein the second subpopulation of primed and expanded T cells having specificity for a viral antigen (e.g. [0069], viral antigen and tumor antigen).
Thus, Bollard et al anticipate the claims.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded and rebutted prior arguments in prior Office Actions.
Claim Rejections - 35 USC § 103
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.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
3. Claims 110-113, 118, 120-121, 123, and 130 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Bollard et al (U.S. 2015/0359876; Applicant’s own work; of record), as applied to Claims 110-113 and 130 above, and in further view of Yousif et al (2013; of record), Hermann et al (WO 17/167959; of record), and Sung et al (2008; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 110 and 130, Bollard et al is considered relevant prior art for having disclosed a method for treating a subject in need of adoptive immunotherapy, the method comprising the step(s) of administering to the subject a cellular composition comprising:
i) a first subpopulation of primed and expanded T cells having specificity for a viral associated antigen;
ii) a second subpopulation of primed and expanded T cells having specificity for a tumor antigen (e.g. [0069], viral antigen and tumor antigen); and
iii) mesenchymal stem cells (e.g. [0082], other cellular products, e.g. mesenchymal stem cells, may be coadministered with the anti-specific T cells according to the invention).
Bollard et al clearly disclosed the T cell composition comprises T cells that recognize a combination of antigens (e.g. [0014] Using Multiple Antigens; [0069], viral antigens in addition to tumor antigens).
Bollard et al disclosed wherein the tumor antigen is a testis cancer tumor antigen, e.g. PRAME [0069-70].
While it is clear that the immunotherapeutic cell composition comprises a subpopulation of primed and expanded T cells having specificity for a tumor antigen (e.g. [0069]), and thus treatment of virus-associated disease [0010], including virus-associated cancers [0011] would be reasonably understood by the ordinary artisan that to include subjects who have cancer, Bollard et al do not disclose ipsis verbis wherein said subjects have cancer.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 110 and 123, Yousif et al is considered relevant prior art for having taught that the art recognized that testis cancer has a viral etiology (e.g. Abstract), including HIV patients (per Bollard et al).
Furthermore, Hermann et al is considered relevant prior art for having disclosed a method of treating cancer in a subject (e.g. pg 4, lines 8-10 and 18-19), e.g. testicular cancer (pg 17, lines 12 and 17), the method comprising the step of administering mesenchymal stem cells combined with tumor-antigen specific T cells, e.g. CAR T cells.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing AdVanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in immunology, virology, and stem cell transplantation. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to treat a subject suffering from cancer with a cellular immunotherapeutic composition comprising:
i) a first subpopulation of primed and expanded T cells having specificity for a viral associated antigen;
ii) a second subpopulation of primed and expanded T cells having specificity for a tumor antigen; and
iii) mesenchymal stem cells,
with a reasonable expectation of success because Applicant’s themselves previously disclosed the use of such a therapeutic cellular composition for the treatment of a subject that may have some form of cancer, e.g. a virus-associated cancer, e.g. testicular cancer [0069-70], whereby those of ordinary skill in the art previously recognized an etiological association and/or causation of testicular cancer with viral disease (Yousif et al), and Hermann et al suggested that MSC cells are to be used in combination with tumor-antigen specific T cells for the treatment of cancer in a subject, as the MSCs are able to enhance the activity of an anti-tumor immunotherapy (e.g. pg 5, lines 1-2), and in experimental mouse models the combined use of MSC and tumor-antigen specific T cells demonstrated synergistic effect (pgs 31-32).
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).
With respect to Claims 111-112, Bollard et al disclosed wherein the tumor antigen is PRAME (e.g. [0069-70]).
With respect to Claims 110 and 113, Bollard et al disclosed wherein the second subpopulation of primed and expanded T cells having specificity for a viral antigen (e.g. [0069], viral antigen and tumor antigen).
With respect to Claim 121, Bollard et al disclosed wherein the subject has or is undergoing immunosuppressive therapy (e.g. [0081]).
With respect to Claim 118, Hermann et al disclosed wherein the MSC subpopulation is
autologous (pg 21, lines 6-13).
With respect to Claim 120, Hermann et al disclosed
wherein the MSC subpopulation is from bone marrow (e.g. pg 1, lines 32-33; pg 30, line 12, “cells were isolated from bone marrow”) or cord blood (pg 3, lines 19-20), and
wherein the MSC subpopulation comprises:
greater than 95% of cells having a positive antigen expression pattern CD105, CD73, and CD90 (pg 1, lines 37-39) and/or
less than 2% of cells having an antigen expression pattern CD45, CD34, CD14, CD19, and HLA-DR (pg 1, lines 37-39).
Sung et al taught that MSCs express CD29, and do not express CD3.
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.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded to and rebutted prior arguments in prior Office Actions.
4. Claim 113 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Bollard et al (U.S. 2015/0359876; Applicant’s own work; of record), Yousif et al (2013; of record), Hermann et al (WO 17/167959; of record), and Sung et al (2008; of record), as applied to Claims 110-113, 118, 120-121, 123, and 130, and in further view of Bollard et al (2016; Applicant’s own work; of record; hereafter Bollard-2), Ip et al (available online May 9, 2018; of record), and Feuchtinger (2008; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Bollard et al does not disclose wherein the viral antigen is a hexon protein of human adenovirus (HAdV).
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 113, Bollard-2 is considered relevant prior art for having taught a method of treating a human subject in need of adoptive immunotherapy, the method comprising the step of administering to the subject a cell composition comprising T cells that recognize a viral antigen (e.g. pg 3332, col. 2, Ex vivo expansion of antigen-specific VSTs; Figure 1; pg 3334, col. 1, Clinical results with VSTs), wherein the viral antigen is a human adenoviral hexon protein antigen (e.g. pg 3332, col. 1, “ADV virion protein hexon and penton”; Table 3).
Similarly, Ip et al is considered relevant prior art for having taught a method of treating a human subject in need of adoptive immunotherapy, the method comprising the step of priming a population of T cells with human adenovirus antigens, thereby generating AdV-specific T cells, and then administering the AdV-specific T cells to said subject.
Ip et al taught wherein the AdV viral antigen is AdV5 hexon peptide (e.g. pg 832, col. 2; AdV5 Hexon PepTivator; pg 835, Table 2).
Ip et al taught that Adenovirus (ADV) reactivation can cause significant morbidity and mortality in children after allogeneic stem cell transplantation. Antiviral drugs can control viremia, but viral clearance requires recovery of cell-mediated immunity. The study demonstrates the safety and feasibility of preemptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy. (Abstract).
Similarly, Feuchtinger et al is considered relevant prior art for having taught a method of treating a human subject in need of adoptive immunotherapy, the method comprising the step of priming a population of T cells with human adenovirus hexon-specific antigens (e.g. Title), thereby generating AdV-specific T cells, and then administering the AdV-specific T cells to said subject. Feuchtinger et al taught Good Manufacturing Practice-compatible generation of hexon-specific T cells comprising the step(s) of priming with HAdV hexon protein and in vitro expansion of hexon-specific cytotoxic T cells (e.g. Abstract).
Feuchtinger et al taught that because there are conserved T-cell epitopes in the HAdV hexon protein, the HAdV hexon-specific T cells are able to show cross-reactive proliferation and functional responses to different HAdV species (e.g. Figure 5, pg 205, col. 2).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first viral antigen, e.g. human adenovirus, as disclosed by Bollard et al, with a second viral antigen, i.e. human adenovirus hexon protein, as taught by Bollard-2, Ip et al, and Feuchtinger et al, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first viral antigen, e.g. human adenovirus, with a second viral antigen, i.e. human adenovirus hexon protein, because Applicant themselves (Bollard-2), Ip et al, and Feuchtinger et al, each successfully demonstrated the ability to manufacture virus-specific T cells (VSTs) directed against human adenovirus hexon protein for methods of treating a human subject in need of adoptive immunotherapy, whereby the VSTs confer protection in vivo after adoptive transfer in 70%-90% of recipients (Bollard-2), manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of safety, feasibility, and clinical efficacy (Ip et al), and that because there are conserved T-cell epitopes in the HAdV hexon protein, the HAdV hexon-specific T cells are able to show cross-reactive proliferation and functional responses to different HAdV species (Feuchtinger et al).
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.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded to and rebutted prior arguments in prior Office Actions.
5. Claims 110, 113, 115-116, and 129 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Bollard et al (U.S. 2015/0359876; Applicant’s own work; of record), Yousif et al (2013; of record), Hermann et al (WO 17/167959; of record), Sung et al (2008; of record), as applied to Claims 110-113 and 130 above, and in further view of Bollard et al (2016; Applicant’s own work; of record; hereafter Bollard-2), Ip et al (available online May 9, 2018; of record), and Feuchtinger (2008; of record), as applied to Claims 110-113, 118, 120-121, 123, and 130 above, and in further view of Reissner et al (WO 17/009853; January 19, 2017; of record), Kang et al (available online March 23, 2018; of record), Tasker et al (WO 17/168135; filed March 27, 2017; of record), Pacesa et al (available online August 18, 2017; of record), and Hermes et al (2016; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Bollard et al disclosed wherein the viral antigen may be an adenoviral antigen (e.g. [0015, 100]), as cytotoxic T cell therapy with donor T cells was previously recognized to prevent and/or treat adenoviral injections after stem cell transplantation.
Bollard-2 taught wherein the viral antigen is a human adenoviral hexon protein antigen (e.g. pg 3332, col. 1, “ADV virion protein hexon and penton”; Table 3).
Ip et al taught wherein the AdV viral antigen is AdV5 hexon peptide (e.g. pg 832, col. 2; AdV5 Hexon PepTivator; pg 835, Table 2).
Feuchtinger et al taught that because there are conserved T-cell epitopes in the HAdV hexon protein, the HAdV hexon-specific T cells are able to show cross-reactive proliferation and functional responses to different HAdV species (e.g. Figure 5, pg 205, col. 2).
Neither Bollard et al, Bollard-2, Ip et al, nor Feuchting et al taught wherein the viral antigen is a hexon protein of human adenovirus, e.g., HAdV-3.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 110, 113, and 115, Reisner et al is considered relevant prior art for having disclosed a method for treating a subject in need of adoptive immunotherapy, the method comprising the step of administering to said subject a population of T cells that recognize a target antigen, e.g. PRAME tumor antigen (pg 6, line 13) or Adenovirus-3 (HADV-3) viral antigen (e.g. pg 6, line 21).
Hermes et al is considered relevant prior art for having taught a method of treating cancer in a subject, wherein the cancer expresses PRAME, the method comprising the step of administering to said subject PRAME-specific cytotoxic T cells (e.g. pg 400, col. 2, “cancer immunotherapy employing specific killing of PRAME-expressing cancer cells by PRAME-specific cytotoxic lymphocytes”).
Kang et al is considered relevant prior art for having taught an epidemiologic study of human adenovirus in allogeneic hematopoietic cell transplantation cancer patient recipients (e.g. pg 2, col. 1), whereupon in all cases of viremia, they were caused only by HAdV-3. Kang et al taught that immunosuppression or T-cell depletion used to reduce GvHD is also a major risk factor for HAdV infection in HSCT recipients (e.g. pg 6, col. 1).
Tasker et al is considered relevant prior art for having disclosed a method of determining cell-mediated immune response competence of a subject, the method comprising the step of incubating T cells from the subject (e.g. pg 5, lines 33-34; pg 13, lines 8-9) with peptide pools, wherein the peptide pools comprise HAdV-3 hexon protein (pg 15, Table 1)
Pacesa et al is considered relevant prior art for having produced anti-viral antibodies directed against HAdV-3 hexon protein fragments (e.g. Abstract; Figure 1), whereby adenoviral infection can be life-threatening to immune-compromised individuals (e.g. pg 2, col. 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first viral antigen, e.g. human adenovirus, as disclosed by Bollard et al, with a second viral antigen, i.e. human adenovirus 3 (HAdV-3) hexon protein, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first viral antigen, e.g. human adenovirus, with a second viral antigen, i.e. human adenovirus 3 (HAdV-3) hexon protein, because Applicant themselves (Bollard et al), Ip et al, and Feuchtinger et al, each successfully demonstrated the ability to manufacture virus-specific T cells (VSTs) directed against human adenovirus hexon protein for methods of treating a human subject in need of adoptive immunotherapy, whereby the VSTs confer protection in vivo after adoptive transfer in 70%-90% of recipients (Bollard-2), manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of safety, feasibility, and clinical efficacy (Ip et al), and that because there are conserved T-cell epitopes in the HAdV hexon protein, the HAdV hexon-specific T cells are able to show cross-reactive proliferation and functional responses to different HAdV species (Feuchtinger et al). Reisner et al disclosed a method for treating a subject in need of adoptive immunotherapy, the method comprising the step of administering to said subject a population of T cells that recognize Adenovirus-3 (HADV-3) viral antigen (e.g. pg 6, line 21), whereby immunosuppression or T-cell depletion used to reduce GvHD is also a major risk factor for HAdV infection in HSCT recipients, and in a study of allogeneic hematopoietic cell transplantation cancer patient recipients, all cases of viremia, they were caused only by HAdV-3 (Kang et al). Those of ordinary skill in the art previously recognized and successfully reduced to practice the use of HAdV-3 hexon protein fragments or peptide pools to generate anti-viral antibodies (Pacesa et al) or incubate with T cells from a subject to elicit antigen-specific immune responses (Tasker et al).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to treat a subject having a cancer that expresses PRAME with tumor antigen-specific T cells (TATs) directed against PRAME and virus-specific T cells (VSTs) directed against HAdV-3 hexon protein and autologous MSCs with a reasonable expectation of success because those of ordinary skill in the art previously recognized that:
i) methods of treating subjects having a cancer that expresses PRAME include adoptive immunotherapy (Bollard et al; Herman et al; Hermes et al);
ii) methods of treating subjects having a cancer, including a cancer that expresses PRAME (Bollard et al), comprises adoptive immunotherapy in combination with MSCs (Bollard et al), including autologous MSCs (Herman et al);
iii) methods of treating subjects having a cancer that expresses PRAME include administration of tumor antigen-specific T cells (TSTs) directed against PRAME and virus-specific T cells (VSTs), including subjects that has or is undergoing immunosuppressive therapy (Bollard et al);
iv) Applicant themselves (Bollard et al), Ip et al, and Feuchtinger et al, each successfully demonstrated the ability to manufacture virus-specific T cells (VSTs) directed against human adenovirus hexon protein for methods of treating a human subject in need of adoptive immunotherapy, including manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation;
v) VSTs confer protection in vivo after adoptive transfer in 70%-90% of recipients (Bollard-2);
vi) those of ordinary skill in the art previously recognized and successfully reduced to practice the use of HAdV-3 hexon protein fragments or peptide pools to generate anti-viral antibodies (Pacesa et al) or incubate with T cells from a subject to elicit antigen-specific immune responses (Tasker et al);
vii) in a study of allogeneic hematopoietic cell transplantation cancer patient recipients, all cases of viremia were caused only by HAdV-3 (Kang et al); and
viii) Reisner et al disclosed a method for treating a subject in need of adoptive immunotherapy, the method comprising the step of administering to said subject a population of T cells that recognize Adenovirus-3 (HADV-3) viral antigen (e.g. pg 6, line 21), whereby immunosuppression or T-cell depletion used to reduce GvHD is also a major risk factor for HAdV infection in HSCT recipients; and
ix) ADV-specific T cells provides early evidence of safety, feasibility, and clinical efficacy (Ip et al), and that because there are conserved T-cell epitopes in the HAdV hexon protein, the HAdV hexon-specific T cells are able to show cross-reactive proliferation and functional responses to different HAdV species (Feuchtinger et al).
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.
Response to Arguments
Applicant iterates prior arguments.
The Examiner has responded to and rebutted prior arguments in prior Office Actions.
Citation of Relevant Prior Art
6. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Feuchtinger (Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation, British J. Haematol. 134: 64-75, 2006; of record) is considered relevant prior art for having taught a method of treating a human subject in need of adoptive immunotherapy, the method comprising the step of priming a population of T cells with human adenovirus antigens, thereby generating AdV-specific T cells, and then administering the AdV-specific T cells to said subject.
Feuchtinger et al taught that HAdV infection is as serious complication following allogeneic stem cell transplantation, and virus-specific donor T cells for adoptive transfer is a new treatment option to confer immunity to patients with HAdV-infection/reactivation, whereby the HAdV-specific T cells show high specificity and markedly reduced alloreactivity in vitro, and that induction of a specific T-cell response through adoptive transfer was feasible and effective, capable of protecting the human subject from HAdV-related complications (Abstract).
Conclusion
7. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638