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 .
Election/Restrictions
Applicant’s election without traverse of Group I, represented by claims 1, 3, 5, and 35-49 in the reply filed on 5/16/2025 is acknowledged.
Claims 50-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 5/16/2025.
Claims 1, 3, 5, and 35-49 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 7/25/2022 and 5/16/2025 are in compliance with 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because Fig. 3B is of such low resolution that it is illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 40 is objected to because of the following informalities: it should recite “TRP1 promoter, or Tyr promoter” on line 4, rather than “TRP1 promoter, Tyr promoter”. Appropriate correction is required.
Claim 43 is objected to because of the following informalities: it should recite “comprise a recombinant virus that comprises” on line 2, rather than “comprise a recombinant virus comprises”. Appropriate correction is required.
Claim 46 is objected to because of the following informalities: it should recite “mesenchymal stem cells (MSCs)” on line 2, rather than “MSCs”. Appropriate correction is required.
Examiner’s Note
Applicant’s amendment of Claim 5 deleted text on lines 1-2, but used the double brackets placed before and after the deleted characters to indicate it, instead of strikethrough. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. R. 1.121(c)(2).
Claim Rejections - 35 USC § 112
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.
Claim 38 is 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 38 includes the limitation “wherein between 20% and 80% of cells comprise the recombinant virus”. However, Claim 38 depends from Claim 35, which indicates “[a] population of mesenchymal lineage precursor or stem cells, wherein said cells are modified to introduce a recombinant virus.” Claim 38 is unclear because it suggests that only a portion of the population of cells may comprise a recombinant virus, whereas Claim 35 indicates that the cells of the population are modified to introduce a recombinant virus.
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 (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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, 35-38, 44-49 are rejected under 35 U.S.C. 103 as being unpatentable over Chang, et al. (WO 2009028870 A2, published 3/5/2009; hereinafter referred to as “Chang”) in view of Russell (Nat Commun. 2018 Nov 27;9(1):5006. Doi: 10.1038/s41467-018-07344-1; hereinafter referred to as “Russell”) as evidenced by Ning, et al. (Biochem Biophys Res Commun. 2011 Sep 23;413(2):353-7. doi: 10.1016/j.bbrc.2011.08.104. Epub 2011 Aug 2; hereinafter referred to as “Ning”).
The claimed invention encompasses a population of mesenchymal lineage precursor or stem cells, wherein said cells are modified to increase expression of Phosphatase and Tensin Homolog deleted on chromosome 10 alpha (PTENα), wherein the increase in expression of PTENα is sufficient to decrease the level of phosphorylated AKT in modified cells, as recited in claim 1. In a specific embodiment, the increase in expression of PTENα is sufficient to enhance killing of tumour cells, and/or enhance migration to tumour cells, as recited in claim 3. In another embodiment, the mesenchymal lineage precursor or stem cells are modified to introduce a recombinant virus which comprises a polynucleotide encoding PTENα, as recited in claim 5. In one embodiment, the tumour cells are breast cancer or brain cancer cells, as recited in claim 45. Alternatively, the mesenchymal lineage precursor or stem cells are MSCs or induced pluripotent stem (iPS) cells, as recited in claim 46. In another embodiment, the population of cells has been culture expanded, as recited in claim 47. In a more specific embodiment, the population of cells has been culture expanded from an isolated population of mesenchymal lineage precursor or stem cells that are STRO-1+, as recited in claim 48.
Another embodiment of the claimed invention encompasses a population of mesenchymal lineage precursor or stem cells, wherein said cells are modified to introduce a recombinant virus which comprises a polynucleotide encoding PTENα, as recited in claim 35. In other embodiments, the recombinant virus is an oncolytic virus, as recited in claim 36, comprises a herpes simplex virus (HSV) backbone, as recited in claim 37. Alternatively, between 20% and 80% of cells comprise the recombinant virus, as recited in claim 38. In a different embodiment, the recombinant virus is a HSV, as recited in claim 44. In another specific embodiment, modification to introduce the virus increases expression of Phosphatase and Tensin Homolog deleted on chromosome 10 alpha (PTENα), wherein the increase in expression of PTENα is sufficient to decrease the level of phosphorylated AKT in modified cells, as recited in claim 49.
The Prior Art
Chang teaches pharmaceutical compositions for preventing or treating brain cancers comprising mesenchymal stem cells (Chang, claim 1), which may have an anti-tumor gene introduced into them, which may be a tumor suppressor gene (Chang, claim 3), such as phosphatase and tensin homolog (PTEN; Chang, claim 4). Chang further teaches that an oncolytic virus such as Herpes simplex virus can be introduced into the mesenchymal stem cells (Chang, claims 13-14). Chang also teaches that MSC were sub-cultivated repeatedly until the MSCS were sufficiently expanded (Chang, p. 23, lines 1-10; Example 2). Ning discloses that STRO-1 is the best-known mesenchymal stem cell-marker (Abstract). However, Chang does not specifically teach that the PTEN is the PTENα isoform, or that PTENα expression is sufficient to decrease the level of phosphorylated AKT in modified cells.
Russell teaches an oncolytic herpes simplex virus that expresses PTENα, which decreases phospho-AKT (S473) levels in U87ΔEGFR cells upon infection (Fig. 2). A single dose of the PTENα-expressing HSV resulted in long term survival in mice bearing intracranial tumors, and priming anticancer T-cell immunity leading to tumor rejection (Russell, Abstract; Figs. 6 & 8-9). Russell further teaches that tumor cells were more sensitive to PTENα-expressing HSV than control HSV at lower MOIs (Russell, Fig. 4b).
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Chang to utilize the PTENα-expressing HSV taught by Chang. Ning discloses that STRO-1 is the best-known mesenchymal stem cell-marker (Abstract), therefore, the MSCs taught by Chang would inherently be STRO-1+. Notably, although Chang does not specifically disclose that between 20% and 80% of cells comprise the recombinant virus, that is inherent to the teachings of Chang, since Chang teaches expansion of its populations, and as these cells would continue to undergo mitosis, 100% only a portion of the cells would remain infected. Further, the quantity of infected cells would be arrived at through routine optimization, since one of skill in the art would need to expand the cell population to the required size prior to use, and that would result in a portion of the cell population lacking the virus. One of ordinary skill in the art would have been motivated to prevent or treat cancers such as brain cancers. One of ordinary skill in the art would have had a reasonable expectation of success because infection of mesenchymal or stem cell precursor cells with oncolytic viruses and PTEN-expressing recombinant viruses, as well as PTENα-expressing herpes simplex viruses were known in the prior art. Therefore, Claims 1, 3, 5, 35-38, 44-49 were prima facie obvious to one of ordinary skill in the art before the priority date of the instant invention.
Claims 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Chang and Russell as evidenced by Ning (supra) as applied to claims 1, 3, 5, 35-38, 44-49 above, and further in view of Kosai, et al. (PGPub US 20140023619 A1, published 1/23/2014, filed 3/24/2011; hereinafter referred to as “Kosai”).
In an alternative embodiment, the polynucleotide encoding PTENα is operatively linked to a tumour specific promoter or an inducible promoter, as recited in claim 39, wherein the tumour specific promoter is a survivin promoter, COX-2 promoter, PSA promoter, CXCR4 promoter, STAT3 promoter, hTERT promoter, AFP promoter, CCKAR promoter, CEA promoter, erbB2 promoter, E2F1 promoter, HE4 promoter, LP promoter, MUC-1 promoter, TRP1 promoter, or Tyr promoter, as recited in claim 40.
The Prior Art
The teachings of Chang and Russell are described above. However, they do not specifically teach the polynucleotide encoding PTENα is operatively linked to a tumour specific promoter or an inducible promoter, such as COX-2, CEA, erbB2, or MUC-1.
Kosai teaches compositions and methods related to viral vectors having promoters that are specifically expressed in cancer stem cells, wherein the vector is used for treatment and diagnosis (Abstract, Kosai, claims). Kosai specifically teaches that the viral vector may be a herpes simplex virus (paras. [0046], [0057]-[0062]). Additionally, Kosai discloses that examples of cancer-specific promoters include COX-2, CEA, erbB2, MUC-1, among many others (para. [0064]).
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Chang to utilize the PTENα-expressing HSV taught by Russell, wherein the PTENα is expressed under the control of a tumour specific promoter such as COX-2, CEA, erbB2, or MUC-1, as taught by Kosai. One of ordinary skill in the art would have been motivated to prevent or treat cancers such as brain cancers. One of ordinary skill in the art would have had a reasonable expectation of success because infection of mesenchymal or stem cell precursor cells with oncolytic viruses and PTEN-expressing recombinant viruses, PTENα-expressing herpes simplex viruses, and control of exogenous genes encoded by herpes simplex virus by cancer-specific promoters were known in the prior art. Therefore, Claims 39-40 were prima facie obvious to one of ordinary skill in the art before the priority date of the instant invention.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Chang and Russell as evidenced by Ning (supra) as applied to claims 1, 3, 5, 35-38, 44-49 above, and further in view of Dobbins (PGPub US 20170368117 A1, published 12/8/2017, filed 12/24/2014; hereinafter referred to as “Dobbins”).
In another embodiment of the claimed invention, the recombinant virus comprises a capsid protein that binds a tumour-specific cell surface molecule, as recited in claim 41.
The Prior Art
The teachings of Chang and Russell are described above. Chang also teaches that adenovirus vectors may be used to deliver the gene of interest to mesenchymal stem cells (p. 18, lines 28-34). However, they do not specifically teach the recombinant virus comprising a capsid protein that binds a tumour-specific cell surface molecule.
Dobbins teaches oncolytic adenoviruses that target multiple receptors upregulated on tumors, the adenoviruses comprising an Ad5/3 fiber with a carboxyl terminus RGD ligand (Abstract, Dobbins, generally). Dobbins further teaches that immunotherapeutic agents, such as GMCSF can be delivered by the oncolytic adenoviruses (para. [0201-0202]; Abstract; Fig. 8).
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Chang to utilize the oncolytic adenovirus taught by Dobbins, wherein the PTENα taught by Russell is the therapeutic agent to be delivered. One of ordinary skill in the art would have been motivated to prevent or treat cancers such as brain cancers. One of ordinary skill in the art would have had a reasonable expectation of success because infection of mesenchymal or stem cell precursor cells with oncolytic viruses and PTEN-expressing recombinant viruses, therapeutic-expressing oncolytic adenoviruses, and recombinant adenovirus comprising a capsid protein that binds a tumour-specific cell surface molecule were known in the prior art. Therefore, Claim 41 was prima facie obvious to one of ordinary skill in the art before the priority date of the instant invention.
Claims 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Chang and Russell as evidenced by Ning (supra) as applied to claims 1, 3, 5, 35-38, 44-49 above, and further in view of Kaur (WO 2018023114 A1, published 2/1/2018, filed 7/29/2016; hereinafter referred to as “Kaur”).
In an alternative embodiment of the claimed invention, the mesenchymal lineage precursor or stem cells are modified to comprise a recombinant virus that comprises a nucleic acid sequence as shown in SEQ ID NO: 1, as recited in claims 42-43.
The Prior Art
The teachings of Chang and Russell are described above. However, they do not specifically teach the recombinant virus comprising a nucleic acid sequence as shown in SEQ ID NO: 1.
Kaur teaches oncolytic viruses expressing PTEN-long, which is represented by SEQ ID NO: 1 (p. 18, para. 78; claims 1, 13-15). Notably, Kaur’s SEQ ID NO: 1 is 100% identical in sequence to SEQ ID NO: 1 of the instant application. Below is an abbreviated portion of the ABSS alignment between Kaur’s SEQ ID NO: 1 and the instant SEQ ID NO: 1:
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It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Chang to utilize a PTENα-expressing HSV taught by Russell, wherein the PTENα is the sequence taught by Kaur. One of ordinary skill in the art would have been motivated to prevent or treat cancers such as brain cancers. One of ordinary skill in the art would have had a reasonable expectation of success because infection of mesenchymal or stem cell precursor cells with oncolytic viruses and PTEN-expressing herpes simplex viruses, and the particular PTEN sequence, SEQ ID NO: 1 were known in the prior art. Therefore, Claims 42-43 were prima facie obvious to one of ordinary skill in the art before the priority date of the instant invention.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet Andres can be reached at 571-272-0867. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671