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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. The amendments filed on 12/05/2025 have been entered.
Reissue: Non-Final Office Action
Status of the Claims
Claims 18-24, 26-30, and 32-34 are currently pending and are the subject of this Office Action (OA). Claims 18-24, 26-30, and 32-34 are newly presented in this reissue application, claim 34 having been added since the last OA.
Procedural Posture
On 01/03/2017: US Patent 9,534,248 issued to Gambhir et al. with claims 1-4.
On 05/18/2023: Applicants filed US Reissue Patent Application 18/320,145 for US Patent 9,534,248.
On 12/23/2024: A non-final Office Action (OA) was mailed rejecting claims 6-18 (all claims pending at that time).
On 06/18/2025: Applicants filed a response to the 12/23/24 OA with arguments and amendments.
On 08/07/2025: A final Office Action was mailed rejecting claims 1-4 and 18-33 (all claims pending at that time).
On 12/05/2025: Applicants filed a Request for Continued Examination (RCE), with arguments and amendments.
Maintenance Fees
Applicant is reminded of the requirement to pay all applicable maintenance fees on the original patent. See MPEP § 1415.01.
Ongoing Duty To Disclose
Applicant(s) is/are reminded of the continuing obligation under 37 CFR 1.178(b), to timely apprise the Office of any prior or concurrent proceeding in which Patent 9,534,248 is or was involved. These proceedings would include any trial at the Patent Trial and Appeal Board, interferences, reissues, reexaminations, supplemental examinations, and litigation.
Applicant is further reminded of the continuing obligation under 37 CFR 1.56, to timely apprise the Office of any information which is material to patentability of the claims under consideration in this reissue application.
These obligations rest with each individual associated with the filing and prosecution of this application for reissue. See also MPEP §§ 1404, 1442.01 and 1442.04.
OBJECTIONS/REJECTIONS WITHDRAWN
The rejection of claim 25 under 35 U.S.C. 251, based on In re Orita, is moot in light of the claim cancellation.
The rejection of claims 26-27 under 35 U.S.C. 112, 1st paragraph/(a), lack of written description, is withdrawn in light of the claim amendments.
The rejection of claims 18, 20, 22-24, and 28-33 under 35 U.S.C. 102(a)(2) is withdrawn in light of the claim amendments.
The rejection of claims 18-24, 28-30, 32, and 33 under 35 U.S.C. 103 is withdrawn in light of the claim amendments.
The double patenting rejections of record have been withdrawn in light of the abandonment of cases 16/223,294 and 18/325,809.
OBJECTIONS/REJECTIONS MAINTAINED
The rejection of claims 18-24, 26-30, and 32-33 under 35 U.S.C. 251, for defective declaration, is maintained as discussed below.
The rejection of claims 18-24 and 26-33 under 35 U.S.C. 251, for failing to meet the original patent requirement, is maintained as discussed below.
Information Disclosure Statement
The reference cited on the information disclosure statement dated 12/05/2025 was considered and has been made of record.
Certificate of Correction
The '248 patent contains a certificate of correction dated 01/03/2017, but there is no copy of this document in the reissue application. Applicants are required to supply a copy of the certificate of correction. See 37 CFR 1.173(a)(1). Applicants must also supply a copy of the claims, including the changes made by the certificate of correction, without markings in this reissue application. See MPEP § 1411.01.
Multiple Reissue Applications
The specification is objected to because it fails to include a proper cross reference to additionally filed reissue application 18/325,809. See 37 CFR 1.177(a): If applicant files more than one application for the reissue of a single patent, each such application must contain or be amended to contain in the first sentence of the specification a notice stating that more than one reissue application has been filed and identifying each of the reissue applications by relationship, application number and filing date. The specification should be amended to indicate that more than one reissue application is filed over issued US Patent 9,534,248, and to provide all of the reissue application numbers, filing dates, and relationships.
An example of the suggested language to be inserted is as follows:
Notice: More than one reissue application has been filed for the reissue of Patent No. 99,999,999. The reissue applications are application number 99/999,994 (the present application); and application number 99/999,995, which is a continuation reissue of Patent No. 99,999,999.
See MPEP § 1451. Since both applications 16/223,294 and 18/325,809 are now abandoned, it is not necessary to amend the specifications in those cases. However, the specification in this application should be amended as above to provide notice of application 18/325,809.
Claim Objections
The amended claim set filed 12/05/2025 is improper. The amendment does not comply with 37 CFR 1.173 which sets forth the manner of making amendments in reissue applications. Specifically:
A. The text of canceled claims 1-4 should not be presented. 37 CFR 1.173(2) states that, “a patent claim or added claim should be canceled by a statement canceling the claim without presentation of the text of the claim.
B. Claims 18-21, 26, 27, 29, 30, 32, and 33 use single brackets to denote deleted matter. Although single brackets are proper to show deleted material in a patented claim, claim 18 is a new claim, not a patented claim. All amendments in reissue claims must be made relative to the patented claims. Since claim 18 is a new claim, it should be presented completely underlined, without showing other markings relative to the prior claim set.
While the improper amendment has been entered and considered, a supplemental paper correctly amending the reissue application is required. An amendment filed after final rejection that fails to comply with 37 CFR 1.173 will not be entered. Appropriate correction is required.
Defective Declaration/Oath
The reissue oath/declaration filed with this application is defective because it fails to properly identify at least one error which is relied upon to support the reissue application. See 37 CFR 1.175 and MPEP § 1414.
The reissue oath/declaration filed with this application is defective (see 37 CFR 1.175 and MPEP § 1414) because of the following:
The declaration by the assignee filed on 6/18/2025 states:
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The 6/18/2025 states that “one error is omission of a claim directed to a composition comprising a vector lacking an origin of replication”, however the pending claims no longer include composition claims at all. Further, claim 5 has been canceled, so the error statement in the declaration is not accurate. The error identified in the declaration is no longer present in this reissue application.
Broadening Reissue
The instant reissue application was filed on 05/18/2023 as a continuation (CON) of reissue application 16/223,394. Reissue application 16/223,294 was filed 12/18/2018, which is within two years of the issue date of US Patent 9,534,248 (issued on 01/03/2017); and has clear intent to broaden a claim.
Claims 18-24, 26-30, and 32-34 are rejected under 35 U.S.C. 251 as being an improper recapture of broadened claimed subject matter surrendered in the application for the patent upon which the present reissue is based.
A broadening aspect is present in the reissue application which was not present in the patent under reissue. The record of the application for the patent shows that the broadening aspect (in the reissue) relates to claimed subject matter that applicant previously surrendered during the prosecution of the application. Accordingly, the narrow scope of the claims in the patent was not an error within the meaning of 35 U.S.C. 251, and the broader scope of claim subject matter surrendered in the application for the patent cannot be recaptured by the filing of the present reissue application.
See Greenliant Systems, Inc. et al v. Xicor LLC, 692 F.3d 1261, 103 USPQ2d 1951 (Fed. Cir. 2012); In re Shahram Mostafazadeh and Joseph O. Smith, 643 F.3d 1353, 98 USPQ2d 1639 (Fed. Cir. 2011); North American Container, Inc. v. Plastipak Packaging, Inc., 415 F.3d 1335, 75 USPQ2d 1545 (Fed. Cir. 2005); Pannu v. Storz Instruments Inc., 258 F.3d 1366, 59 USPQ2d 1597 (Fed. Cir. 2001); Hester Industries, Inc. v. Stein, Inc., 142 F.3d 1472, 46 USPQ2d 1641 (Fed. Cir. 1998); In re Clement, 131 F.3d 1464, 45 USPQ2d 1161 (Fed. Cir. 1997); Ball Corp. v. United States, 729 F.2d 1429, 1436, 221 USPQ 289, 295 (Fed. Cir. 1984).
In accordance with MPEP 1412.02 (and case law cited therein) we apply the recapture rule as a three-step process:
(1) Determine whether, and in what respect, the reissue claims are broader in scope than the original patent claims.
(2) Determine whether the broader aspects of the reissue claims related to subject matter surrendered in the original prosecution; and
(3) Determine whether the reissue claims were materially narrowed in other respects, so that the claims may not have been enlarged, and hence avoid the recapture rule.
In the instant case,
(1) Reissue claims 18-24, 26-30, and 32-34 are broader in scope than the original patent claims.
All of the original (patented) claims required SEQ ID NO: 1. For example, claim 3 was drawn to a method of detecting a tumor cell by delivering a recombinant minicircle vector comprising the nucleic acid sequence of SEQ ID NO: 1. Claim 18 of this reissue does not require a minicircle vector, and does not require the delivered DNA molecule to have the nucleic acid sequence of SEQ ID NO: 1. Thus, instant claim 18 is broader than any of the patented claims.
(2) The broader aspect of the reissue of claims 18-24, 26-30, and 32-34 is related to subject matter surrendered in the original prosecution.
During prosecution of application 14/480,861 that issued as US Patent 9,534,248, original claim 1 recited a minicircle vector encoding a polypeptide and operably linked to a tumor-specific promoter (i.e., original claim 1 did not require SEQ ID NO: 1). The examiner rejected the claims under 35 U.S.C. 102 and 103, indicating claim 7 (which recited SEQ ID NO: 1) as allowable if rewritten in dependent form in the 05/20/2016 OA. In order to overcome the claim rejections, applicant cancelled all claims that did not require SEQ ID NO: 1 and amended the withdrawn method claims to require SEQ ID NO: 1 (see the claims filed 08/17/2016). In doing so, applicants specifically noted that patentability (including rejoinder of withdrawn claims) was predicated on limiting the claims to SEQ ID NO: 1 (see p. 3 of the remarks dated 08/17/2016). The amended claims presented with the instant reissue no longer require SEQ ID NO: 1, which is precisely the broader scope that applicants surrendered in the prosecution of application 14/480,861, which issued at US Patent 9,534,248, to gain the allowance of claims 1-4.
(3) There is no evidence of record that the reissue claims were materially narrowed in other respects so that the claims may not have been enlarged, and hence avoid the recapture rule. Applicants have not demonstrated how the instant claims have been narrowed in order to avoid recapture.
Original Patent (Maintained)
The following is a quotation of the first paragraph of 35 U.S.C. 251:
(a) IN GENERAL.—Whenever any patent is, through error, deemed wholly or partly inoperative or invalid, by reason of a defective specification or drawing, or by reason of the patentee claiming more or less than he had a right to claim in the patent, the Director shall, on the surrender of such patent and the payment of the fee required by law, reissue the patent for the invention disclosed in the original patent, and in accordance with a new and amended application, for the unexpired part of the term of the original patent. No new matter shall be introduced into the application for reissue.
Claims 18-24, 26-30, and 32-34 are rejected under 35 U.S.C. 251, for claiming subject matter that does not meet the original patent requirement.
MPEP 1412.01 states that the reissue claims must be for the same invention as that disclosed as being the invention of the original patent. MPEP 1412.01 further provides guidelines for determining whether the reissue claims are "for the invention disclosed in the original patent" as:
(A) the claims presented in the reissue application are described in the original patent specification and enabled by the original patent specification such that 35 U.S.C. 112, first paragraph is satisfied; and
(B) nothing in the original patent specification indicates an intent not to claim the subject matter of the claims presented in the reissue application; and
(C) the newly claimed invention is clearly and unequivocally disclosed in the specification as a separate invention with the claimed combination of features.
The presence of the disclosure in the original patent should evidence that applicant intended to claim or that applicant considered the material now claimed to be the invention.
Claims 18-24, 26-30, and 32-34 of this reissue application do not meet the "original patent" requirement under 35 USC 251 because the '248 patent specification does not clearly and unequivocally disclose the claimed invention.
Amended independent claim 18 recites a method comprising a) administering to a subject a composition comprising "a non-viral circular DNA molecule that lacks an antibiotic resistance gene and is replication incompatible" and the non-viral circular DNA molecule comprises a gene expression promoter of human origin operably linked to a nucleic acid sequence encoding an expression product. It also requires that the non-viral circular DNA molecule is less immunogenic than another non-viral circular DNA molecule containing a viral or bacterial promoter, and it requires that during the method, expression of the expression product is increased in a cancer cell exactly 2-fold compared to a non-cancer cell as measured by in vitro chemiluminescent assay.
The '248 patent as originally filed discloses recombinant tumor specific nucleic acid minicircle1 vectors comprising a tumor specific gene expression promoter operably linked to a nucleic acid sequence encoding a reporter (detectable) gene, and a method of detecting a tumor cell in a sample from a human or non-human subject by delivering the disclosed minicircle vectors (abstract; col. 2, lines 21-26; col. 3, lines 21-54; col. 15, line 61 to col. 16, line 3; col. 19; lines 56-60; col. 20, lines 13-17; col. 20, line 66 to col. 21, line 8; col. 21, lines 6-8; col. 21, lines 33-38; col. 22, lines 24-29; col. 23, lines 34-67; Examples 1-9; SEQ ID NO: 1, vector maps in Fig. 2A, Figs. 1, 7-10; schematic map of the minicircle vector construct MC-pSurv-SEAP-WPRE-SV40PolyA and original claims). The '248 patent defines that that the minicircle vectors are plasmids that lack a bacterial backbone (col. 4, lines 24-26).
Independent claim 18 eliminates the requirement that the claimed non-viral circular DNA molecule lacks a bacterial backbone. The '248 patent only disclosed “tumor specific minicircle vectors”, and the phrase “tumor specific minicircle vector” was repetitively recited in the Title, the abstract, the summary of the invention, the drawings, examples and the entirety of the specification of the patent and original claims.
Consistent with MPEP 1412.01, nowhere does the written description or drawings disclose non-viral circular DNA molecule other than the minicircle vectors which lack a bacterial backbone. Even if a person of ordinary skill in the art would understand that constructing the newly claimed, “non-viral circular DNA molecule that lacks an antibiotic resistance gene and is replication incompatible” would have been within the level of ordinary skill, that is insufficient to meet the original patent requirement because the '248 patent only discloses a minicircle system that lacks a bacterial backbone.
Independent claim 18 also introduces a new requirement that the non-viral circular DNA molecule, which contains a human promoter, is less immunogenic than a non-viral circular DNA molecule that contains a viral or bacterial promoter. The '248 patent discloses that SEAP as a reporter protein has “reduced or zero immunogenic potential in patients similar to what has been shown with murine SEAP … in immunocompetent mice.” (col. 19, lines 29-32) The instant claims, however, are not limited to a SEAP promoter, and the '248 patent contains no teaching about viral or bacterial promoters at column 19, lines 29-32. Furthermore, the '248 patent discloses that viruses and (bacterial) plasmids are immunogenic (col. 21, lines 18-25), but it says nothing there about the source of the promoter being the cause of immunogenicity.
Independent claim 18 also requires that the expression of the expression product in the cancer cell is increased by exactly 2-fold compared to expression in the non-cancer cell. The '248 patent discloses an “approximate 4.5-fold increase in [bioluminescence] signal” in mice administered minicircle vectors (col. 7, lines 65-67), but the '248 patent does not compare bioluminescence in cancer cells relative to non-cancer cells. The precise value “2-fold” appears nowhere in the ’248 patent.
Since the original disclosure of the '248 patent fails to clearly and unequivocally disclose the claimed method, claims 18-24, 26-30, and 32-34 violate the original patent requirement of 35 USC 251.
CLAIM REJECTIONS - 35 USC § 251
Claims 18-24, 26-30, and 32-34 are rejected as being based upon a defective reissue declaration under 35 U.S.C. 251 as set forth above. See 37 CFR 1.175.
The nature of the defect(s) in the declaration is set forth in the discussion above in this Office Action.
Claim Rejections - 35 USC § 112(a) (or pre-AIA , 1st Paragraph)
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 18-24, 26-30, and 32-34 are rejected under 35 U.S.C. 112, first paragraph or 35 U.S.C. 112(a), 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(s), at the time the application was filed, had possession of the claimed invention.
Specifically, the newly added limitations: 1) "replication incompatible", 2) wherein the non-viral circular DNA molecule is less immunogenic than another non-viral circular DNA molecule containing a promoter of viral or bacterial origin, and 3) wherein the expression of the expression product is increased in the cancer cell by 2-fold as compared to the non-cancer cell are not described in the specification as-filed.
Regarding 1) above, the phrase "replication incompatible" does not appear anywhere in the specification. For the purposes of this Office Action, the term/phrase "replication incompatible" will be interpreted to be met by a vector lacking an origin of replication. Regarding 2) above, lower immunogenicity is discussed in the specification generally with respect to non-viral vectors being less immunogenic than viral vectors and unmethylated CpG sequences in the prokaryotic backbone (col. 20, lines 47-63; col. 21, lines 9-32). The specification also teaches that the SEAP protein may have reduced or zero immunogenic potential due to its human origin (col. 19, lines 13-36). However, it is not clear where support exists for a promoter (of human origin) having reduced immunogenicity relative to a promoter of viral or bacterial origin as presently claimed. Regarding 3) above, nowhere does the specification teach an expression product increase of 2-fold in cancer cells relative to non-cancer cells.
Claim Rejections - 35 USC § 112(b) or (pre-AIA ) 35 USC § 112 (2nd Par.)
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.
Claims 18-24, 26-30, and 32-34 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 pre-AIA the applicant regards as the invention.
Claims 18-24, 26-30, and 32-34 are indefinite in the recitation "replication incompatible" in claims 18 and 29. This term does not appear in the specification, and its meaning is not readily apparent. This term could refer to the lack of some component(s) required for replication (e.g., an origin of replication) or could refer to other functional meanings, for example a cell containing the claimed minicircle might be rendered incapable of replicating some or all of its genetic material or may be rendered incapable of driving cell division. As such, "replication incompatible" is new, undefined terminology that renders the claims indefinite. See MPEP § 2173.05(a).
Claim Rejections - 35 USC § 103
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 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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 18, 20-24, 26-30, 32, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over SZALAY (2014/0140959; Priority to 10/05/2012) in view of YANG (Yang, L., et al. Gene Ther. (2004), 11(15); 1215-1223).
As amended, the method of claim 18 comprises a) administering intravenously to a human a composition comprising a replication incompatible non-viral circular DNA molecule lacking an antibiotic resistance gene, wherein the non-viral circular DNA molecule comprises a promoter of human origin that selectively drives expression of a reporter polypeptide in a cancer cell vs in a non-cancer cell; and b) expressing the reporter polypeptide in a cancer cell in the subject. The non-viral circular DNA molecule is less immunogenic than one having a promoter of viral or bacterial origin, and the expression of the reporter polypeptide is increased by 2-fold in the cancer cell vs the non-cancer cell.
Szalay discloses a diagnostic and therapeutic method of administering a composition comprising a nucleic acid molecule encoding an enzyme (a reporter), delivering the nucleic acid to tumor cells in a subject (e.g., a human), and expressing the reporter in the cells (title; abstract; [0005], [0014], [0036], [0225]). Szalay teaches bioluminescent reporter genes/markers such as luciferase ([0012], [0336], [0377], [0379], [0383]-[0386]; Table 4). Szalay teaches inserting the nucleic acid encoding the enzyme into a non-viral minicircle vector ([0014], [0139], [0273], [0331], claim 19). Szalay teaches operably linking the nucleic acid to a tumor specific promoter ([0027], [0068]-[0169], [0347], [0349]), meaning the tumor-specific promoter has from about 2- to about 900-fold more ability to express a nucleic acid sequence operatively linked thereto in a tumor cell compared to in a normal cell ([0169]), which encompasses the requirement in claim 18 for 2-fold increased expression. Szalay teaches that the nucleic acid molecule is administered intravenously (systemically) to a human subject ([0035], [0552]) with a tumor/cancer ([0036]).
Szalay expressly teaches that the minicircle vectors (one type of non-viral circular vector) do not include all of the requisite elements for viral replication, packaging and/or expression ([0331]). This teaching is consistent with the definition of minicircles recognized in the art as described in the '248 patent, which establishes that minicircles lack an antibiotic resistance gene and lack an origin of replication (see col. 10, lines 57-61 and col. 18, lines 61-63 of the '248 patent). Accordingly, the minicircle vectors of Szalay are non-viral circular DNA molecules which lack an antibiotic resistance gene and an origin of replication (i.e., one potential interpretation of “replication incompatible”).
Szalay teaches human promoters ([0274], [0328], [0438]; claim 43) and tumor-specific promoters including the promoter from the human survivin gene (i.e., a promoter of human origin) ([0349]). However, Szalay does not teach human promoters, particularly tumor-specific human promoters, with sufficient specificity to be anticipatory.
Yang reports on tumor-specific gene expression using the survivin promoter (title; abstract). Yang demonstrates that the human survivin promoter was highly active in human tumor cells but not in normal cells (abstract; p. 2, 3rd par.; p. 5, 3rd par.; Fig. 1; Discussion). Yang teaches that hypoxic regions in tumors are common (p. 3), and the activity of human survivin promoter is further increased in hypoxic tumor cells (p. 4, top section; Figs. 3-4). Yang teaches that the survivin promoter was effective to drive expression of luciferase (Results, first section, bridging pgs. 2-3; Figs. 1-2). Yang teaches advantages of the survivin promoter over the CMV promoter because CMV induces apoptosis in both tumor and normal cells, but survivin preferentially induces apoptosis in tumor cells over normal cells (p. 4, bottom section; Fig. 5). Thus, Yang provides motivation to select a tumor-specific promoter such as the human survivin promoter over a viral promoter such as CMV.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to have selected a human promoter such as the human survivin promoter for use in Szalay's minicircles. One would have been motivated to do so since Yang teaches the human survivin promoter is a tumor-specific promoter that has advantages over other commonly used promoters such as CMV. One would have had a high expectation of success since Szalay teaches use of the luciferase gene as a reporter/marker and since Yang establishes that the survivin promoter successfully drives expression of luciferase in tumor cells (pgs. 2-3, Results), and since Szalay teaches the survivin promoter as a suitable tumor-specific promoter ([0349]).
Regarding the non-viral circular DNA molecule being less immunogenic than one having a promoter of viral or bacterial origin, this limitation describes a property that results from the use of a human promoter compared to a viral or bacterial promoter (e.g., see the '248 patent at col. 19, lines 25-33; col. 21, lines 9-28). Thus, selection of the human survivin promoter taught by Szalay meets this limitation.
Regarding the use of a chemiluminescent assay, Szalay teaches administering energy, including luminous energy after expression of the reporter gene ([0029]-[0030], [0173]) to detect said reporter gene ([0012], [0037]-[0038], [0159], [0173], [0383]-[0386]).
Regarding claims 20, 21, 30, 32, and 33, Szalay teaches that the reporter molecule is detectable intracellularly or extracellularly ([0160], [0173], [0840]), for example using diagnostic imaging in blood cancers ([0036], [0253], [0220], [0280]).
Regarding claims 22-23, Szalay teaches that the nucleic acid molecule is administered to a subject who has cancer ([0036]), and the nucleic acid operatively linked to a tumor specific promoter expressed in a tumor cell ([0169]).
Regarding claim 24, Szalay teaches that the composition administered to the patient is a pharmaceutical composition comprising a pharmaceutically acceptable excipient ([0009], [0042], [0235], [0514]).
Regarding claim 26, Szalay teaches the nucleic acids may encode one or more expression products ([0042], [0156], [0248], [0401]).
Regarding claim 27, Szalay teaches, inter alia, cytosine deaminase, carboxylesterase, carboxypeptidases, cytochrome P-450, etc. ([0401]; Table 4).
Regarding the transfection agent in claim 28, Szalay teaches the use of a delivery vehicle that mediates its entry into cells. The exemplary agents include cationic liposomes, lipids, lipoproteins, and/or synthetic polymers (refers to transfection agent) ([0275]-[0276], [0282], [0553]).
Regarding the double-stranded DNA molecule in claim 29, Szalay teaches that the nucleic acid molecule is a double-stranded DNA ([0139], [0273]).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over SZALAY (2014/0140959; Priority to 10/05/2012) and YANG (Yang, L., et al. Gene Ther. (2004), 11(15); 1215-1223) as applied to claims 18, 20-24, 26-30, 32, and 33 above, and further in view of WARRAM (Warram, J. M. et al. Mol. Imaging Biol. (2011), 13(3); 452-461).
The teachings of Szalay and Yang are presented supra, and are incorporated herein. Szalay teaches secreted alkaline phosphatase as a suitable gene product (Table 4), but does not expressly teach secreted embryonic alkaline phosphatase (SEAP).
Warram teaches a novel diagnostic system for in vivo early detection, identification, and monitoring of ovarian/breast cancer leading to a better treatment outcome (title; abstract). Warram teaches dual reporter adenoviral vector (Ad5/3-Id1-SEAP-Id1-mCherry) with cancer specific Id1 promoter driving expression of a blood-based screening reporter (secreted embryonic alkaline phosphatase (SEAP)) and a fluorescent imaging reporter (mCherry) (p. 452, Materials and Methods, pgs. 454, 458). Warram teaches that the dual reporter adenovirus vector Ad5/3-Id1-SEAP-Id1-mCherry was administered to mice, and the blood plasma levels of SEAP were detected in the samples from mice (Experiment 5, pgs. 455-458). The SEAP reporter has the unusual qualities of being extremely heat stable and resistant to the phosphatase inhibitor L-homoarginine (allowing endogenous alkaline phosphatase activity to be eliminated under these conditions), and allows non-invasive detection in blood with high sensitivity (SEAP detection is extremely sensitive with sensitivity in the picogram/ml range) (p. 454). Further, Warram teaches the human origin of SEAP allows the use of this reporter in a blood-based medium without generating an immune response (p. 454).
In light of these teachings, an artisan would have found it obvious to use SEAP as a reporter in the minicircle vectors of Szalay. An artisan would have been motivated to use SEAP as a reporter to allow endogenous alkaline phosphatase activity to be eliminated at 65 °C and using L-homoarginine, non-invasive detection in blood with high sensitivity, and a blood-based assay without generating an immune response. Doing so, particularly with a tumor-specific promoter such as survivin (per Yang), would also address Szalay's objective of diagnosing tumors in humans in a non-invasive manner. One would have had a high expectation of success since Szalay teaches secreted alkaline phosphatase as a suitable gene product.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over SZALAY (2014/0140959; Priority to 10/05/2012) and YANG (Yang, L., et al. Gene Ther. (2004), 11(15); 1215-1223) as applied to claims 18, 20-24, 26-30, 32, and 33 above, and further in view of WARRAM (Warram, J. M. et al. Mol. Imaging Biol. (2011), 13(3); 452-461) and Great EscAPe SEAP Manual (Clontech User Manual; Pub. Nov. 9, 2009).
The teachings of Szalay, Yang, and Warram are presented supra, and are incorporated herein. Warram teaches the use a fluorescent assay to measure SEAP expression (i.e., the New Fluorescent Great EscAPE SEAP Assay from Clontech), but does not expressly teach a chemiluminescent assay for SEAP.
However, chemiluminescent assays for SEAP were commercially available prior to the instant application. For example, the Great EscAPe SEAP assay kit from Clontech featured both fluorescent and chemiluminescent assays (see the Table of Contents, sections IV and V; Fig. 1; pgs. 10-13). Thus, either type of SEAP assay would have been obvious. The choice of fluorescent or chemiluminescent assay would have been within the skill of the artisan, and would have been made based on the available equipment (e.g., a luminometer or fluorometer).
Response to Arguments
Applicants' arguments have been fully considered but are not persuasive. Regarding the rejection under 35 U.S.C. § 251 for a defective declaration, applicants provide a statement in the response attempting to correct the defective declaration (response, pg. 10).
The statement provided by applicants on p. 10 of the response is not accurate since it still references "a claim directed to a composition". All pending claims are method claims, and no claims directed to compositions are pending in this case.
Regarding the rejection under 35 U.S.C. § 251 for failing to meet the original patent requirement, applicants argue that the use of the term "minicircle" throughout the original patent encompasses a broader class of non-viral DNA molecules (response, pgs. 13-14).
However, the original patent was limited to "minicircle" vectors, and applicant defined "minicircles" to have certain characteristics. Specifically, the '248 patent specification defines that that a minicircle vector lacks a bacterial backbone (col. 4, lines 24-26, 51-54; Fig. 2A; col. 15, lines 58-60; col. 18, lines 49-53; col. 20, lines 53-59) and is a non-replicating, non-viral vector which lacks an OriP (col. 10, lines 36-47, 57-61; col. 15, lines 58-60; col. 18, lines 43-47). The original patent lacks any disclosure of a minicircle vector that has an origin of replication. Further, applicants’ amendments have not addressed the requirement that the minicircles lack a bacterial backbone, which was another original patent issue that was raised in the prior OA.
Claim 18 as amended also introduces new original patent issues. The '248 patent discloses that SEAP as a reporter protein has “reduced or zero immunogenic potential in patients similar to what has been shown with murine SEAP … in immunocompetent mice.” (col. 19, lines 29-32) The instant claims, however, are not limited to a SEAP promoter, and the '248 patent contains no teaching about viral or bacterial promoters at column 19, lines 29-32. Furthermore, the '248 patent discloses that viruses and (bacterial) plasmids are immunogenic (col. 21, lines 18-25), but it says nothing there about the source of the promoter being the cause of immunogenicity. Thus, the new requirement that the non-viral circular DNA molecule, which contains a human promoter, is less immunogenic than a non-viral circular DNA molecule that contains a viral or bacterial promoter is fails to meet the original patent requirement.
Independent claim 18 also requires that the expression of the expression product in the cancer cell is increased by exactly 2-fold compared to expression in the non-cancer cell. The '248 patent discloses an “approximate 4.5-fold increase in [bioluminescence] signal” in mice administered minicircle vectors (col. 7, lines 65-67), but the '248 patent does not compare bioluminescence in cancer cells relative to non-cancer cells. The precise value “2-fold” appears nowhere in the ’248 patent.
Regarding the art rejections of record, applicants allege that Szalay does not teach various newly inserted limitations (Response pgs. 17-20). These points are addressed by the newly imposed rejection under 35 U.S.C. 103 over Szalay in view of Yang. Applicants’ concern that Szalay does not render use of the survivin promoter obvious is addressed by the teachings of Yang as set forth in the rejection.
Conclusion
Claims 18-24, 26-30, and 32-34 are rejected. No claims are currently allowable.
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/Kevin S Orwig/Patent Reexamination Specialist, Art Unit 3991
Conferees:
/Lora E Barnhart Driscoll/Patent Reexamination Specialist, Art Unit 3991
/Patricia L Engle/SPRS, Art Unit 3991
1 The '248 patent specification defines that that a minicircle vector lacks a bacterial backbone (col. 4, lines 24-26, 51-54; Fig. 2A; col. 15, lines 58-60; col. 18, lines 49-53; col. 20, lines 53-59) and is a non-replicating, non-viral vector which lacks an OriP (col. 10, lines 36-47, 57-61; col. 15, lines 58-60; col. 18, lines 43-47).
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