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 .
Detailed Action
This action is in response to the papers filed May 1, 2026.
Amendments
Applicant's amendments, filed May 1, 2026, is acknowledged. Applicant has cancelled Claims 2-22, and amended Claim 1.
Claim 1 is pending and under consideration.
Priority
This application is a 371 of PCT/EP2017/061961 filed on May 18, 2017.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).
A certified copy of the foreign patent application Spain 201631473 filed on November 17, 2016 is provided with the instant application.
A certified English translation of said foreign patent application was submitted into the application on April 6, 2022.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on May 1, 2026 that has been considered.
The information disclosure statement filed May 1, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations 7 and 11 contain embedded hyperlinks, which should be removed.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claim 1 is objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The multiple ‘wherein’ clauses should each be separated by line indentation.
Appropriate correction is required.
2. Claim 1 is objected to because of the following informalities:
The claim is unnecessarily verbose, and instead can be written more concisely.
The first ‘wherein’ clause is not needed if Applicant simply amends “oncolytic adenovirus” (line 4) to instead recite “oncolytic human adenovirus serotype 5”, for example.
The third ‘wherein’ clause is not needed if Applicant simply amends “hyaluronidase enzyme” (line 5) to instead recite “human hyaluronidase enzyme PH20”, for example.
The sixth ‘wherein’ clause is not needed if Applicant simply amends “administering” (line 3) to instead recite “administering by intravitreal injection”, for example.
The seventh ‘wherein’ clause is not needed if Applicant simply amends “retinoblastoma” (lines 1-2) to instead recite “retinoblastoma resistant to conventional chemotherapy and/or radiotherapy treatment”, for example.
The eighth ‘wherein’ clause is not needed if Applicant simply amends “subject” (line 2) to instead recite “a human subject”, for example.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
3. The prior rejections of Claims 4 and 22 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in light of Applicant’s cancellation of the claims.
4. The prior rejection of Claims 1 and 4-10 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in light of Applicant’s amendments to the independent claim, and cancellation of the dependent claims.
5. The prior rejection of Claims 8-9 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the independent claim, and cancellation of the dependent claims.
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.
6. Claim 1 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Cascallo Piqueras et al (CA 2761183, 2010; Applicant’s own work not cited in an IDS; of record), in view of Ji et al (Exp. Eye Res. 89: 193-199, 2009; of record in IDS), Szalay et al (U.S. 2014/0087362; of record), Fueyo et al (U.S. 2006/0147420; of record), Song et al (Int. J. Mol. Sci. 13(9): 10736-10749; 2012; of record in IDS), Chen et al (Cancer Letters 307(1): 93-103, 2011; abstract only; of record), and Ildefonso et al (2010; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Cascallo Piqueras et al is considered relevant prior art for having disclosed an oncolytic adenovirus comprising:
i) a sequence encoding a hyaluronidase enzyme; and
ii) replication machinery specific for tumor cells (pg 10, lines 8-13).
Cascallo Piqueras et al disclosed the use of the oncolytic adenovirus for the treatment of cancer, e.g. head and neck, melanoma, ovarian, colorectal, pancreatic, and hepatocellular carcinomas, as such had already been in practice in clinical medicine with very promising results (pg 3, lines 14-17).
Cascallo Piqueras et al do not disclose use of the oncolytic adenovirus for the treatment of retinoblastoma.
However, prior to the effective filing date of the instantly claimed invention, Ji et al is considered relevant prior art for having taught a method of treating retinoblastoma in a subject in need thereof, the method comprising the steps of:
administering to the subject a composition comprising an oncolytic adenovirus comprising replication machinery specific for tumor cells (Abstract, “CRAd replication occurred exclusively in human RB cells, but not primary human retinal pigment epithelial cells”), wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Similarly, Szalay et al is considered relevant prior art for having disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus [0036, 468], wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296]. Szalay et al disclosed a cancer model system using cancer stem cells that were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Fueyo et al is considered relevant prior art for having disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene (Title), wherein the therapeutic transgene encodes relaxin [0105] or hyaluronidase [0106]. Fueyo et al disclosed that malignant tumors are intrinsically resistant and/or refractory to conventional therapies [0067].
Song et al is considered relevant prior art for having taught a method of treating retinoblastoma, wherein the retinoblastoma is a retinoblastoma resistant to conventional chemotherapy (pg 10737, Introduction, “problems of drug resistance”, “has demonstrated encouraging results in refractory malignancies”; keywords), the method comprising the step of administering an oncolytic adenovirus (Title), whereby the oncolytic adenovirus “overcomes chemoresistance” (pg 10745).
With respect to the oncolytic adenovirus being human serotype 5,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the oncolytic adenovirus is generated from a human adenovirus serotype 5 (pg 25, Example 8, lines 20-23; claim 4).
Ji et al taught wherein the oncolytic adenovirus is generated from a human adenovirus serotype 5 (pg 194, col. 1, Materials and Methods, “serotype 5 adenoviruses”).
Fueyo et al disclosed wherein adenovirus serotype 5 is the preferred starting material, being a human adenovirus [0119].
Chen et al taught wherein the SG600 oncolytic adenovirus is a serotype 5 (Abstract).
With respect to the modified capsid,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the oncolytic adenovirus has the capsid modified such that the binding domain 91-KKTK-94 of the heparin sulfates present in the adenovirus fibre have been replaced by the domain 91-RGDK-94 (pg 25, Example 8, lines 20-23).
With respect to the human hyaluronidase enzyme PH20,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the hyaluronidase enzyme is the human hyaluronidase enzyme PH20 (pg 21, Example 4).
With respect to the nucleic acid sequence encoding PH20,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the oncolytic adenovirus is ICOVIR17 (e.g. pg 6, line 1), whereby the sequence that encodes a hyaluronidase enzyme from which nucleotides corresponding to 1471 to 1527 have been deleted (pg 18, Example 1; Figure 2A). Instant specification discloses VCN-01 comprises SEQ ID NO:1, from which nucleotides 1471-1527 have been deleted, whereby said sequence that encodes a hyaluronidase enzyme was obtained from ICOVIR17 (Example 1).
With respect to the replication machinery,
Applicant themselves (Cascallo Piqueras et al) previously disclosed the replication machinery specific for tumor cells is defective replication machinery that can be complemented in tumor cells by both defective copies of the Rb1 gene, more specifically, wherein the defective replication machinery that can be complemented in tumor cells by both defective copies of the Rb1 gene comprises:
i) the deletion delta-24 in the sequence coding for the E1a protein, and
ii) an insertion of four E2F-1 binding sites and one Sp1 binding site into the endogenous promoter of E1a to control the expression of E1a (pg 10, lines 8-13).
Fueyo et al disclosed wherein the oncolytic adenovirus uses the delta-24 system [0124], as it produces an E1A protein that cannot bind Rb [0128].
Song et al taught wherein the SG600 comprises the replication machinery specific for tumor cells is defective replication machinery that can be complemented in tumor cells by both defective copies of the Rb1 gene, and comprises the deletion delta-24 in the sequence coding for the E1a protein (pg 10737, Introduction).
With respect to the intravitreal administration,
Ji et al taught wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Szalay et al disclosed wherein said oncolytic virus being administered ocularly or intravitreally [0296].
Ildefonso et al successfully demonstrated intravitreal administration of an oncolytic adenovirus to human patients suffering from retinoblastoma (e.g. pg 1887, col. 2, “patients received intravitreal injections”).
With respect to the retinoblastoma being resistant to conventional chemotherapy and/or radiotherapy,
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus, wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma, wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin, said oncolytic virus being administered ocularly or intravitreally, and wherein the cancer stem cells were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Fueyo et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene, wherein the therapeutic transgene encodes relaxin or hyaluronidase, and wherein malignant tumors are intrinsically resistant and/or refractory to conventional therapies [0067].
Song et al taught a method of treating retinoblastoma, wherein the retinoblastoma is a retinoblastoma resistant to conventional chemotherapy (pg 10737, Introduction, “problems of drug resistance”, “has demonstrated encouraging results in refractory malignancies”; keywords), the method comprising the step of administering an oncolytic adenovirus, whereby the oncolytic adenovirus “overcomes chemoresistance” (pg 10745).
With respect to the subject being human,
Applicant themselves (Cascallo Piqueras et al) previously disclosed the use of the oncolytic adenovirus for the treatment of cancer, e.g. head and neck, melanoma, ovarian, colorectal, pancreatic, and hepatocellular carcinomas, as such had already been in practice in clinical medicine (syn. human) with very promising results (pg 3, lines 14-17).
Ji et al taught the mouse subject is a model of human retinoblastoma, and that the oncolytic adenovirus is useful for the treatment of human retinoblastoma (e.g. Abstract; pg 196, col. 2, Discussion).
Szalay et al disclosed wherein the subject is mouse or human (e.g. [0013], “subjects include.., particularly humans”; [0075], “an exemplary primate is a human”; [0076], “Typically, a patient refers to a human subject”).
Fueyo et al disclosed the subject is human (e.g. [0167], “for human administration”; Example 5, “patients in a phase I clinical trial”).
Song et al taught the in vitro cell culture using human retinoblastoma cells (e.g. pg 2, Methods, 3.3 Cell Lines, “human retinoblastoma cell line”) is a model of human retinoblastoma, and that the oncolytic adenovirus is useful for the treatment of human retinoblastoma.
Chen et al taught the in vitro cell culture using human hepatocellular carcinoma cells (e.g. pg 2, Methods, 2.1, Cell Lines, “human HCC cell lines”) is a model of human hepatocellular carcinoma and that the oncolytic adenovirus is useful for the treatment of human hepatocellular carcinoma.
Ildefonso et al successfully reduced to practice intraocular administration of an oncolytic adenoviral vector to the eyes of human patients suffering from retinoblastoma (entire paper).
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 molecular biology, virology, and cancer biology. 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); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); 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 cancer being treated with the ICOVIR17 oncolytic adenovirus of Cascallo Piqueras et al with a second cancer, to wit, retinoblastoma, as taught by Ji 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 cancer with a second cancer, to wit, retinoblastoma, being treated with the ICOVIR17 oncolytic adenovirus because Ji et al successfully demonstrated the ability of oncolytic adenoviruses that selectively replicate in tumor cells to treat retinoblastoma in an animal model system.
Ildefonso et al successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Furthermore, Szalay et al disclosed oncolytic adenoviruses for the treatment of proliferative disorders or tumors, wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296], and Fueyo et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene, wherein the therapeutic transgene encodes relaxin or hyaluronidase. Thus, the ordinary artisan previously recognized the scientific and technical concepts that both relaxin and hyaluronidase improved oncolytic adenoviral spread within tumor matrix, thereby improving antitumor efficacy, whereby relaxin and hyaluronidase are substitutable therapeutic transgenes.
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 substitute a first retinoblastoma with a second retinoblastoma, to wit, a retinoblastoma resistant to chemotherapy, as taught by Song et al, in a method of treating retinoblastoma in a subject 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 retinoblastoma with a second retinoblastoma, to wit, a retinoblastoma resistant to chemotherapy, being treated with the ICOVIR17 oncolytic adenovirus because Song et al successfully demonstrated the ability of oncolytic adenoviruses that selectively replicate in tumor cells to treat retinoblastoma resistant to chemotherapy. Song et al taught that “Combined treatment with an oncolytic adenovirus and chemotherapy presents a promising novel treatment strategy for cancer and is rapidly advancing toward clinical use in many malignancies.” (pg 10744, Discussion). Song et al taught that the oncolytic adenovirus “overcomes chemoresistance”, that “viro-chemo combination therapy is a feasible and potentially promising approach for the treatment of retinoblastoma” (pg 10745), whereby viro-chemo combination therapy “exerted a synergistic antitumor effect (Abstract).
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 argues that the field of oncolytic adenovirus therapy is highly unpredictable.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant claim is enormously broad for failing to recite the dosage of the oncolytic adenovirus that is to be administered to the human subject, encompassing values as low as 10^1, or 10^2, oncolytic adenovirus particles.
Applicant cancelled prior recitation of at least 3x10^9 oncolytic adenovirus particles.
Thus, instant Claim 1 is prima facie vastly broader in scope, at least 10 orders of magnitude less than the secondary considerations presented in the Piqueras Declaration which apparently did not work (para 6, Figure 3, table, Patient 1, 2x10^9 pfu, “without clear evidence of tumor seed reduction”) filed April 6, 2022.
As a second matter, all that is required by the claimed method is some amount of treatment, however minor that might be.
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus, wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma, wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin, said oncolytic virus being administered ocularly or intravitreally, and wherein the cancer stem cells were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Fueyo et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene, wherein the therapeutic transgene encodes relaxin or hyaluronidase, and wherein malignant tumors are intrinsically resistant and/or refractory to conventional therapies [0067].
Song et al taught a method of treating retinoblastoma, wherein the retinoblastoma is a retinoblastoma resistant to conventional chemotherapy (pg 10737, Introduction, “problems of drug resistance”, “has demonstrated encouraging results in refractory malignancies”; keywords), the method comprising the step of administering an oncolytic adenovirus, whereby the oncolytic adenovirus “overcomes chemoresistance” (pg 10745).
Ildefonso et al successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Thus, in the field of oncolytic adenovirus therapy for the treatment of retinoblastoma, those of ordinary skill in the art would have possessed a reasonable expectation of success that Applicant’s prior-disclosed VCN-01 adenovirus would have some efficacy for the treatment of retinoblastoma.
As a third matter, the Examiner provides the following references to rebut applicant’s arguments regarding the state of the prior art regarding oncolytic adenovirus therapy. Note: the reference is not considered a part of the 103 rejection but is solely provided to rebut applicant’s argument(s).
Podhajcer et al (U.S. Patent 9,056,133 (June, 2015)) claim a method of treating cancer in a patient (syn. human) comprising the step of administering to said patient an oncolytic adenovirus (claim 1), wherein the cancer is selected from ovarian cancer, pancreatic cancer (as disclosed by Applicant), gastric cancer, a non-small cell lung cancer (as disclosed by Applicant), small cell lung cancer (as disclosed by Applicant), primary peritoneal cancer, hepatocarcinoma, melanoma (as disclosed by Applicant), retinoblastoma, breast tumor, colorectal carcinoma (as disclosed by Applicant), leukemia, lymphoma, brain tumor, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues Wilm's tumor, astrocytoma, glioblastoma, neuroblastoma, ovarian carcinoma, osteosarcoma, renal cancer, or head and neck cancer (claim 11).
Patented claims are considered enabled and predictable with a reasonable expectation of success. Thus, in the field of oncolytic adenovirus therapy, including for the treatment of retinoblastoma, those of ordinary skill in the art would have possessed a reasonable expectation of success and predictability that an oncolytic adenovirus capable of treating one or more first cancers would also have therapeutic efficacy for the treatment of retinoblastoma.
Applicant argues that ONYX-015, Pexa-Vec, CG0070, and DNX-2401 in combination with antibody immunotherapy evidence unpredictability in the field of oncolytic adenoviruses.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant’s own citation that ONXY-015 (oncolytic adenovirus) “demonstrated viral replication within tumors” and “has…modest efficacy” clearly evidences at least some degree of predictability and anti-tumor efficacy.
Applicant’s citation of Pexa-Vec (oncolytic vaccinia virus, not adenovirus) clinical trial abstract provides no information as to what the oncolytic vaccinia virus is, in fact, able to achieve.
The Examiner cites Breitbach et al (The emerging therapeutic potential of the oncolytic immunotherapeutic Pexa-Vec (JX-594), Oncolytic Virotherapy 4: 25-31, 2015) who contradicts Applicant, whereby Breitbach et al clearly state:
“Pexa-Vec has been shown to selectively infect and amplify within tumors (termed oncolysis)” (e.g. pg 26, col. 2);
“functional anticancer immunity in the context of Pexa-Vec treatment was demonstrated in…patients”, “patients who survived the longest had the highest CDC (antibody-mediated complement-dependent cytotoxicity)”, “Reproducible CDC activity was also observed in a Phase II study”, “Pexa-Vec has demonstrated acute antivascular effects”, resulting in “functional reduction in tumor perfusion”, “Phase II study exhibited an acute reduction in tumor perfusion” (e.g. pg 27, col. 1-2); and
“Acute debulking of tumors secondary to oncolysis and vascular targeting are followed by an adaptive antitumor immune response that may impact both existing and new tumor development” (e.g. pg 27, col. 1-2).
Thus, here too, the ordinary artisan recognized at least some degree of predictability and anti-tumor efficacy.
Applicant’s own citation that CG0070 (oncolytic adenovirus) demonstrated “antibladder cancer activity” clearly evidences at least some degree of predictability and anti-tumor efficacy.
To the extent Applicant argues that CG0070 demonstrated response rates that varied across patients, the Examiner notes that the instantly claimed invention suffers the same deficiencies of variable response rates depending on the patient(s), as evidenced by the Piqueras Declaration filed April 6, 2022, e.g. para 6, table, Patient 1, 2x10^9 pfu, “without clear evidence of tumor seed reduction”).
Applicant’s citation of DNX-2401 in combination with antibody immunotherapy is not on point because that particular trial was designed to address the combination therapy protocol. Rather, the article clearly states that in a phase 1 clinical trial, DNX-2401 itself “induced cell death initially by direct oncolysis and subsequently by antitumor response…” (e.g. pg 1371, joining para).
Thus, here too, the ordinary artisan recognized at least some degree of predictability and anti-tumor efficacy.
Applicant argues that Kuroda et al (2014), Peters et al (2020), McKenna et al (2020, and Appleton et al (2025) further evidence unpredictability in the field.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Instant claims are not required to achieve the “improved outcomes [that] generally require combination approaches” (per Kuroda et al). All that is required by the claimed method is some amount of treatment, however minor that might be. The cited prior art clearly taught that adenoviruses are capable of treating retinoblastoma.
Instant claims are not required to achieve the argued “complete tumor response and long-term cure” (per Peters et al).
McKenna et al and Appleton et al, expressing concern over the gap between preclinical and clinical studies, is contradicted by:
Fueyo et al disclosed the subject is human (e.g. [0167], “for human administration”; Example 5, “patients in a phase I clinical trial”);
Song et al taught the in vitro cell culture using human retinoblastoma cells (e.g. pg 2, Methods, 3.3 Cell Lines, “human retinoblastoma cell line”) is a model of human retinoblastoma, and that the oncolytic adenovirus is useful for the treatment of human retinoblastoma; and, most importantly,
Ildefonso et al successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Applicant argues that the claimed method addresses a long-felt, but unmet need.
Applicant’s argument(s) has been fully considered, but is not persuasive. Per Ex parte Richard J. McCann, 2008-0785, May 29, 2008, establishing long-felt need requires objective evidence that an art-recognized problem existed in the art for a long period of time without solution. In particular, the evidence must show that the need was a persistent one that was recognized by those of ordinary skill in the art. In re Gershon, 372 F.2d 535,539 (CCPA 1967). The relevance of long-felt need and the failure of others to the issue of obviousness depend on several factors.
First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. Orthopedic Equipment Co. v. All Orthopedic Appliances, Inc., 707 F.2d 1376 (Fed. Cir. 1983); see also In re Gershon, 372 F.2d 535,539 (CCPA 1967).
Upon review of all of the evidence of long-felt need submitted by the Appellant we have no idea of exactly when the articulated problem, viz, failure of ‘human oncolytic adenovirus serotype 5 encoding PH20 to treat retinoblastoma resistant to conventional chemotherapy and/or radiotherapy’, was first identified. As such, we have no way of knowing just how long the need for a solution to the problem existed. "[L]ong-felt need is analyzed as of the date of an articulated identified problem and evidence of efforts to solve that problem." Texas Instruments, Znc. v. ZTC, 988 F.2d 1165, 1178 (Fed. Cir. 1993).
The declarations submitted by the Appellant demonstrate only that the need for a solution--VCN-01, human oncolytic adenovirus serotype 5 encoding PH20-- to the articulated problem-- treatment of retinoblastoma resistant to conventional chemotherapy and/or radiotherapy-- existed as of November 17, 2016, the day on which foreign application SPAIN 201631473 was filed. This is not evidence of a "long-felt" need nor does it evince that the need was a persistent one in the art. Orthopedic Equipment, 707 F.2d 1376; see also In re Gershon, 372 F.2d at 539. Further, the Appellant has proffered no persuasive evidence that others in the industry had made attempts to solve the articulated problem and failed.
Second, the long-felt need must not have been satisfied by another before the invention by applicant. Newel1 Companies v. Kenney Mfg. Co., 864 F.2d 757,768 (Fed. Cir. 1988) ("[O]nce another supplied the key element, there was no long-felt need or, indeed, a problem to be solved.")
Ji et al taught a method of treating retinoblastoma in a subject in need thereof, the method comprising the steps of administering to the subject a composition comprising an oncolytic adenovirus comprising replication machinery specific for tumor cells (Abstract, “CRAd replication occurred exclusively in human RB cells, but not primary human retinal pigment epithelial cells”), wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus [0036, 468], wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296]. Szalay et al disclosed a cancer model system using cancer stem cells that were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Ildefonso et al (2010) successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Third, the invention must in fact satisfy the longfelt need. In re Cavanagh, 436 F.2d 491 (CCPA 1971). "[L]ong-felt need is analyzed as of the date of an articulated identified problem and evidence of efforts to solve that problem." Texas Instruments, Inc. v. ITC, 988 F.2d 1165, 1178 (Fed. Cir. 1993).
As a first matter, instant claim is enormously broad for failing to recite the dosage of the oncolytic adenovirus that is to be administered to the human subject, encompassing values as low as 10^1, or 10^2, oncolytic adenovirus particles.
Applicant cancelled prior recitation of at least 3x10^9 oncolytic adenovirus particles.
Thus, instant Claim 1 is prima facie vastly broader in scope, at least 10 orders of magnitude less than the secondary considerations presented in the Piqueras Declaration which apparently did not work (para 6, Figure 3, table, Patient 1, 2x10^9 pfu, “without clear evidence of tumor seed reduction”) filed April 6, 2022.
Applicant argues that no oncolytic adenoviruses have been approved for retinoblastoma, and the lack of regulatory approval, despite decades of research and clinical investigation, underscores the failure of prior efforts and the unpredictable nature of the field.
Applicant’s argument(s) has been fully considered, but is not persuasive. The instantly claimed invention is not required to be FDA-approved. Furthermore, the Office must confine its review of patent applications to the statutory requirements of the patent law. Other agencies of the government have been assigned the responsibility of ensuring conformance to standards established by statute for the advertisement, use, sale or distribution of drugs. See MPEP §2107.03
Applicant argues that Ildefonso et al is directed to an adenoviral vector expressing thymidine kinase. It is not an oncolytic adenovirus, but rather a suicide gene approach.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant themselves (Cascallo Piqueras et al) previously disclosed an oncolytic adenovirus comprising:
i) a sequence encoding a hyaluronidase enzyme; and
ii) replication machinery specific for tumor cells (pg 10, lines 8-13).
Cascallo Piqueras et al disclosed the use of the oncolytic adenovirus for the treatment of cancer, e.g. head and neck, melanoma, ovarian, colorectal, pancreatic, and hepatocellular carcinomas, as such had already been in practice in clinical medicine with very promising results (pg 3, lines 14-17).
Ji et al taught a method of treating retinoblastoma in a subject in need thereof, the method comprising the steps of administering to the subject a composition comprising an oncolytic adenovirus comprising replication machinery specific for tumor cells (Abstract, “CRAd replication occurred exclusively in human RB cells, but not primary human retinal pigment epithelial cells”), wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus [0036, 468], wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296]. Szalay et al disclosed a cancer model system using cancer stem cells that were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
The art recognizes that the Ad-RSVtk vector of Ildefonso et al selectively replicates in tumor cells and is oncolytic.
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Applicant argues that because all but one child eventually was treated to enucleate the diseased eye in Ildefonso et al, the authors did not successfully demonstrate treating human patients suffering from retinoblastoma.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instantly recited “treating retinoblastoma” and/or “reducing metastases” is recited at a high level of generality, and thus encompasses any therapeutic effect, however minor that might be.
Instant claims do not prohibit or otherwise exclude enucleation of a patient’s eye after treatment with the oncolytic adenovirus, per the needs of the patient.
Ildefonso et al (2010) successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Absent objective evidence to the contrary, the ‘complete eradication’ of retinoblastoma tumor seeds is reasonably considered to fulfill instant recitations “treating retinoblastoma” and/or “reducing metastases”, whereby those of ordinary skill in the art would immediately recognize that by reducing and/or eradicating tumor seeds, one is also reducing and/or eradicating metastases potential because tumor burden is also reduced/eradicated, per natural law of cell biology.
Applicant argues that Rautsi et al (2008) taught that suicide gene therapy based on HSV-tk and ganciclovir suffers from a lack of efficacy in clinical use.
Applicant’s argument(s) has been fully considered, but is not persuasive. Ildefonso et al (2010) successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
The instantly claimed invention is not required to be FDA-approved. Furthermore, the Office must confine its review of patent applications to the statutory requirements of the patent law. Other agencies of the government have been assigned the responsibility of ensuring conformance to standards established by statute for the advertisement, use, sale or distribution of drugs. See MPEP §2107.03
Applicant argues that Ji et al and Ildefonso et al use replicating adenoviruses expressing an HSVtk suicide gene.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Applicant’s argument is not on point. The substantive issue is whether or not, as of the filing date of the instantly claimed invention, one of ordinary skill in the art would have possessed a reasonable expectation of success that Applicant’s prior disclosed VCN-01 adenovirus would be predictably able to treat retinoblastoma in a human subject.
Ji et al taught a method of treating retinoblastoma in a subject in need thereof, the method comprising the steps of administering to the subject a composition comprising an oncolytic adenovirus comprising replication machinery specific for tumor cells (Abstract, “CRAd replication occurred exclusively in human RB cells, but not primary human retinal pigment epithelial cells”), wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus [0036, 468], wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296]. Szalay et al disclosed a cancer model system using cancer stem cells that were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Ildefonso et al (2010) successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
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 cancer being treated with the ICOVIR17 oncolytic adenovirus of Cascallo Piqueras et al with a second cancer, to wit, retinoblastoma, as taught by Ji 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).”
Applicant argues that Ildefonso et al, Ji et al, and Song et al do not address treatment resistance.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus, wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma, wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin, said oncolytic virus being administered ocularly or intravitreally, and wherein the cancer stem cells were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Fueyo et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene, wherein the therapeutic transgene encodes relaxin or hyaluronidase, and wherein malignant tumors are intrinsically resistant and/or refractory to conventional therapies [0067].
Song et al taught a method of treating retinoblastoma, wherein the retinoblastoma is a retinoblastoma resistant to conventional chemotherapy (pg 10737, Introduction, “problems of drug resistance”, “has demonstrated encouraging results in refractory malignancies”; keywords), the method comprising the step of administering an oncolytic adenovirus, whereby the oncolytic adenovirus “overcomes chemoresistance” (pg 10745).
Applicant argues that the 2022 Cascallo Declaration establishes that Applicant surprisingly found that intravitreal injection of the claimed viral particle concentration of the claimed oncolytic adenovirus demonstrated efficacy in treating a retinoblastoma that is resistant to conventional chemotherapy and/or radiotherapy.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, Applicant’s secondary consideration was achieved using the VCN-01 oncolytic adenovirus (e.g. 2022 Cascallo Declaration, para’s 3-8). However, those of ordinary skill in the art immediately recognize that the genus of structurally diverse oncolytic adenoviruses recited in the independent Claim 1 is vastly larger in scope than the VCN-01 embodiment (e.g. specification, Example 1) which comprises:
i) adenovirus serotype 5 (Claim 5);
ii) the RGD capsid modification (Claim 10);
iii) the human hyaluronidase enzyme PH20 (Claim 6) in which nt1471-1527 have been deleted (Claim 7);
iv) the delta24 E1A mutant protein, insertion of four E2F-1 binding sites and 1 Sp1 binding site into the endogenous E1a promoter (Claim 9); and
v) the pharmaceutically acceptable excipient (Claim 22).
Thus, asserted secondary considerations are not commensurate in scope to the breadth of the independent claim.
As a second matter, Applicant’s secondary consideration was achieved using the at least 2x10^10 virus particles of the VCN-01 oncolytic adenovirus (e.g. 2022 Cascallo Declaration, para 6; Figure 3), as the 2x10^9 resulted in “necrosis without clear evidence of tumor seed reduction”). Rather, it was the 2x10^10 virus particle treatment group (only 3 patients) that “showed a response to VCN-01 treatment”.
Thus, here too, the asserted secondary considerations are not commensurate in scope to the breadth of the independent claim.
As a third matter, Applicant’s secondary consideration was achieved using the at least 2x10^10 virus particles of the VCN-01 oncolytic adenovirus in human patients (e.g. 2022 Cascallo Declaration, para 3; clinical trial, patients:children). While the instant specification supports administration of 3x10^9 virus particles of the VCN-01 oncolytic adenovirus in non-human subjects, to wit, mice (Table 6; pg 21, line 8, “a total content of 3x10^9 virus particles”), instant independent Claim 1 is broader in scope for reciting “at least [no upper limit] 3x10^9 virus particles”. Instant specification does not support intravitreal administration of at least 2x10^10 virus particles of the VCN-01 oncolytic adenovirus in non-human and/or human subjects.
Nevertheless, Ildefonso et al taught administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines), whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Thus, those of ordinary skill in the art previously recognized scientific and clinical technical concepts of, and successfully reduced to practice, the intravitreal administration of therapeutic oncolytic adenoviruses in an amount greater than the de minimus of 3x10^9 virus particles to human patients in a method of treating retinoblastoma.
Applicant themselves (Cascallo Piqueras et al) disclosed administering to the tumor a pharmaceutical composition comprising a pharmaceutically acceptable carrier at least 1x10^8, 2x10^9, or 5x10^10 oncolytic adenovirus particles.
Thus, it is unclear how the asserted secondary considerations are surprising or unexpected. All that is required by the independent claim is to treat the retinoblastoma, which is what the cite prior art taught/disclosed with a reasonable expectation of success.
Applicant iterates prior arguments.
The Examiner has rebutted the prior arguments in prior Office Actions.
7. Claim 1 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Cascallo Piqueras et al (CA 2761183, 2010; Applicant’s own work not cited in an IDS; of record), in view of Ji et al (Exp. Eye Res. 89: 193-199, 2009; of record in IDS), Szalay et al (U.S. 2014/0087362; of record), Fueyo et al (U.S. 2006/0147420; of record), Song et al (Int. J. Mol. Sci. 13(9): 10736-10749; 2012; of record in IDS), Chen et al (Cancer Letters 307(1): 93-103, 2011; abstract only; of record), Ildefonso et al (2010; of record), and Podhajcer et al (U.S. Patent 9,056,133).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Cascallo Piqueras et al is considered relevant prior art for having disclosed an oncolytic adenovirus comprising:
i) a sequence encoding a hyaluronidase enzyme; and
ii) replication machinery specific for tumor cells (pg 10, lines 8-13).
Cascallo Piqueras et al disclosed the use of the oncolytic adenovirus for the treatment of cancer, e.g. head and neck, melanoma, ovarian, colorectal, pancreatic, and hepatocellular carcinomas, as such had already been in practice in clinical medicine with very promising results (pg 3, lines 14-17).
Cascallo Piqueras et al do not disclose use of the oncolytic adenovirus for the treatment of retinoblastoma.
However, prior to the effective filing date of the instantly claimed invention, Ji et al is considered relevant prior art for having taught a method of treating retinoblastoma in a subject in need thereof, the method comprising the steps of:
administering to the subject a composition comprising an oncolytic adenovirus comprising replication machinery specific for tumor cells (Abstract, “CRAd replication occurred exclusively in human RB cells, but not primary human retinal pigment epithelial cells”), wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Similarly, Szalay et al is considered relevant prior art for having disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus [0036, 468], wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296]. Szalay et al disclosed a cancer model system using cancer stem cells that were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Fueyo et al is considered relevant prior art for having disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene (Title), wherein the therapeutic transgene encodes relaxin [0105] or hyaluronidase [0106]. Fueyo et al disclosed that malignant tumors are intrinsically resistant and/or refractory to conventional therapies [0067].
Song et al is considered relevant prior art for having taught a method of treating retinoblastoma, wherein the retinoblastoma is a retinoblastoma resistant to conventional chemotherapy (pg 10737, Introduction, “problems of drug resistance”, “has demonstrated encouraging results in refractory malignancies”; keywords), the method comprising the step of administering an oncolytic adenovirus (Title), whereby the oncolytic adenovirus “overcomes chemoresistance” (pg 10745).
Applicant (Cascallo Piqueras et al) previously disclosed the use of the oncolytic adenovirus for the treatment of cancer, e.g. head and neck, melanoma, ovarian, colorectal, pancreatic, and hepatocellular carcinomas, as such had already been in practice in clinical medicine with very promising results (pg 3, lines 14-17).
Applicant (Cascallo Piqueras et al) previously disclosed the use of the oncolytic adenovirus expressing PH20 hyaluronidase for the treatment of cancer, including, but not limited to, melanoma, pancreatic cancer, colon cancer, and lung cancer (e.g. pg 12, lines 23-25).
Podhajcer et al is considered relevant prior art for having claimed a method of treating cancer in a patient (syn. human) comprising the step of administering to said patient an oncolytic adenovirus (claim 1), wherein the cancer is selected from ovarian cancer, pancreatic cancer (as disclosed by Applicant), gastric cancer, a non-small cell lung cancer (as disclosed by Applicant), small cell lung cancer (as disclosed by Applicant), primary peritoneal cancer, hepatocarcinoma, melanoma (as disclosed by Applicant), retinoblastoma, breast tumor, colorectal carcinoma (as disclosed by Applicant), leukemia, lymphoma, brain tumor, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues Wilm's tumor, astrocytoma, glioblastoma, neuroblastoma, ovarian carcinoma, osteosarcoma, renal cancer, or head and neck cancer (claim 11).
Patented claims are considered enabled and predictable with a reasonable expectation of success.
Thus, in the field of oncolytic adenovirus therapy, including for the treatment of retinoblastoma, those of ordinary skill in the art would have possessed a reasonable expectation of success and predictability that an oncolytic adenovirus capable of treating one or more first cancers would also have some efficacy for the treatment of retinoblastoma.
With respect to the oncolytic adenovirus being human serotype 5,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the oncolytic adenovirus is generated from a human adenovirus serotype 5 (pg 25, Example 8, lines 20-23; claim 4).
Ji et al taught wherein the oncolytic adenovirus is generated from a human adenovirus serotype 5 (pg 194, col. 1, Materials and Methods, “serotype 5 adenoviruses”).
Fueyo et al disclosed wherein adenovirus serotype 5 is the preferred starting material, being a human adenovirus [0119].
Chen et al taught wherein the SG600 oncolytic adenovirus is a serotype 5 (Abstract).
Podhajcer et al disclosed wherein the oncolytic adenovirus (e.g. col. 16, line 62, “oncolytic activity of AV25CDC 5/3 adenovirus”) is serotype 5 (e.g. col. 13, lines 49-50).
With respect to the modified capsid,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the oncolytic adenovirus has the capsid modified such that the binding domain 91-KKTK-94 of the heparin sulfates present in the adenovirus fibre have been replaced by the domain 91-RGDK-94 (pg 25, Example 8, lines 20-23).
Podhajcer et al disclosed wherein the oncolytic adenovirus is serotype 5 with a modified capsid (e.g. col. 14, line 34, “chimeric fiber 5/3”).
With respect to the human hyaluronidase enzyme PH20,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the hyaluronidase enzyme is the human hyaluronidase enzyme PH20 (pg 21, Example 4).
With respect to the nucleic acid sequence encoding PH20,
Applicant themselves (Cascallo Piqueras et al) previously disclosed wherein the oncolytic adenovirus is ICOVIR17 (e.g. pg 6, line 1), whereby the sequence that encodes a hyaluronidase enzyme from which nucleotides corresponding to 1471 to 1527 have been deleted (pg 18, Example 1; Figure 2A). Instant specification discloses VCN-01 comprises SEQ ID NO:1, from which nucleotides 1471-1527 have been deleted, whereby said sequence that encodes a hyaluronidase enzyme was obtained from ICOVIR17 (Example 1).
With respect to the replication machinery,
Applicant themselves (Cascallo Piqueras et al) previously disclosed the replication machinery specific for tumor cells is defective replication machinery that can be complemented in tumor cells by both defective copies of the Rb1 gene, more specifically, wherein the defective replication machinery that can be complemented in tumor cells by both defective copies of the Rb1 gene comprises:
i) the deletion delta-24 in the sequence coding for the E1a protein, and
ii) an insertion of four E2F-1 binding sites and one Sp1 binding site into the endogenous promoter of E1a to control the expression of E1a (pg 10, lines 8-13).
Fueyo et al disclosed wherein the oncolytic adenovirus uses the delta-24 system [0124], as it produces an E1A protein that cannot bind Rb [0128].
Song et al taught wherein the SG600 comprises the replication machinery specific for tumor cells is defective replication machinery that can be complemented in tumor cells by both defective copies of the Rb1 gene, and comprises the deletion delta-24 in the sequence coding for the E1a protein (pg 10737, Introduction).
With respect to the intravitreal administration,
Ji et al taught wherein the oncolytic adenovirus composition is administered by intraocular injection (pg 195, col. 2, “intraocular injections”).
Szalay et al disclosed wherein said oncolytic virus being administered ocularly or intravitreally [0296].
Ildefonso et al successfully demonstrated intravitreal administration of an oncolytic adenovirus to human patients suffering from retinoblastoma (e.g. pg 1887, col. 2, “patients received intravitreal injections”).
With respect to the retinoblastoma being resistant to conventional chemotherapy and/or radiotherapy,
Szalay et al disclosed oncolytic viruses for the treatment of proliferative disorders or tumors, wherein the oncolytic virus may be an oncolytic adenovirus, wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma, wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin, said oncolytic virus being administered ocularly or intravitreally, and wherein the cancer stem cells were resistant to chemotherapy or ionizing radiation ([0256-259], Example 25).
Fueyo et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene, wherein the therapeutic transgene encodes relaxin or hyaluronidase, and wherein malignant tumors are intrinsically resistant and/or refractory to conventional therapies [0067].
Song et al taught a method of treating retinoblastoma, wherein the retinoblastoma is a retinoblastoma resistant to conventional chemotherapy (pg 10737, Introduction, “problems of drug resistance”, “has demonstrated encouraging results in refractory malignancies”; keywords), the method comprising the step of administering an oncolytic adenovirus, whereby the oncolytic adenovirus “overcomes chemoresistance” (pg 10745).
With respect to the subject being human,
Applicant themselves (Cascallo Piqueras et al) previously disclosed the use of the oncolytic adenovirus for the treatment of cancer, e.g. head and neck, melanoma, ovarian, colorectal, pancreatic, and hepatocellular carcinomas, as such had already been in practice in clinical medicine (syn. human) with very promising results (pg 3, lines 14-17).
Ji et al taught the mouse subject is a model of human retinoblastoma, and that the oncolytic adenovirus is useful for the treatment of human retinoblastoma (e.g. Abstract; pg 196, col. 2, Discussion).
Szalay et al disclosed wherein the subject is mouse or human (e.g. [0013], “subjects include.., particularly humans”; [0075], “an exemplary primate is a human”; [0076], “Typically, a patient refers to a human subject”).
Fueyo et al disclosed the subject is human (e.g. [0167], “for human administration”; Example 5, “patients in a phase I clinical trial”).
Song et al taught the in vitro cell culture using human retinoblastoma cells (e.g. pg 2, Methods, 3.3 Cell Lines, “human retinoblastoma cell line”) is a model of human retinoblastoma, and that the oncolytic adenovirus is useful for the treatment of human retinoblastoma.
Chen et al taught the in vitro cell culture using human hepatocellular carcinoma cells (e.g. pg 2, Methods, 2.1, Cell Lines, “human HCC cell lines”) is a model of human hepatocellular carcinoma and that the oncolytic adenovirus is useful for the treatment of human hepatocellular carcinoma.
Ildefonso et al successfully reduced to practice intraocular administration of an oncolytic adenoviral vector to the eyes of human patients suffering from retinoblastoma (entire paper).
Podhajcer et al disclosed wherein the patient is human (e.g. col. 7, “administered to a patient suffering from cancer”; col. 8, “Human use”; col. 19, line 17, “real patient situations”; claim 10, “a patient in need”).
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 molecular biology, virology, and cancer biology. 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); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); 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 cancer being treated with the ICOVIR17 oncolytic adenovirus of Cascallo Piqueras et al with a second cancer, to wit, retinoblastoma, as taught by Ji 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 cancer with a second cancer, to wit, retinoblastoma, being treated with the ICOVIR17 oncolytic adenovirus because Ji et al successfully demonstrated the ability of oncolytic adenoviruses that selectively replicate in tumor cells to treat retinoblastoma in an animal model system.
Ildefonso et al successfully demonstrated administering via intravitreal injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 2.5x10^10 or 1x10^11 oncolytic adenovirus particles in a human clinical trial method of treating retinoblastoma (e.g. pg 1887, col. 2, last 2 lines)., whereby “the targeted vitreous seeds were completely eradicated in all children who received [intravitreally administered oncolytic adenovirus]” (e.g. pg 1886, col. 1).
Furthermore, Szalay et al disclosed oncolytic adenoviruses for the treatment of proliferative disorders or tumors, wherein the proliferative disorder or tumor may be a retinal disease, e.g. eye cancer/retinoblastoma [0150, 567], wherein said oncolytic virus may encode a cell matrix-degrading enzyme, e.g. relaxin ([0448], Table 5]), said oncolytic virus being administered ocularly or intravitreally [0296], and Fueyo et al disclosed a method of treating cancer in a subject, the method comprising the step of administering to said subject an oncolytic adenovirus comprising a therapeutic transgene, wherein the therapeutic transgene encodes relaxin or hyaluronidase. Thus, the ordinary artisan previously recognized the scientific and technical concepts that both relaxin and hyaluronidase improved oncolytic adenoviral spread within tumor matrix, thereby improving antitumor efficacy, whereby relaxin and hyaluronidase are substitutable therapeutic transgenes.
Further still, Podhajcer et al claimed a method of treating cancer in a patient (syn. human) comprising the step of administering to said patient an oncolytic adenovirus (claim 1), wherein the cancer is selected from ovarian cancer, pancreatic cancer (as disclosed by Applicant), gastric cancer, a non-small cell lung cancer (as disclosed by Applicant), small cell lung cancer (as disclosed by Applicant), primary peritoneal cancer, hepatocarcinoma, melanoma (as disclosed by Applicant), retinoblastoma, breast tumor, colorectal carcinoma (as disclosed by Applicant), leukemia, lymphoma, brain tumor, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues Wilm's tumor, astrocytoma, glioblastoma, neuroblastoma, ovarian carcinoma, osteosarcoma, renal cancer, or head and neck cancer (claim 11).
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).”
Patented claims are considered enabled and predictable with a reasonable expectation of success.
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 substitute a first retinoblastoma with a second retinoblastoma, to wit, a retinoblastoma resistant to chemotherapy, as taught by Song et al, in a method of treating retinoblastoma in a subject 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 retinoblastoma with a second retinoblastoma, to wit, a retinoblastoma resistant to chemotherapy, being treated with the ICOVIR17 oncolytic adenovirus because Song et al successfully demonstrated the ability of oncolytic adenoviruses that selectively replicate in tumor cells to treat retinoblastoma resistant to chemotherapy. Song et al taught that “Combined treatment with an oncolytic adenovirus and chemotherapy presents a promising novel treatment strategy for cancer and is rapidly advancing toward clinical use in many malignancies.” (pg 10744, Discussion). Song et al taught that the oncolytic adenovirus “overcomes chemoresistance”, that “viro-chemo combination therapy is a feasible and potentially promising approach for the treatment of retinoblastoma” (pg 10745), whereby viro-chemo combination therapy “exerted a synergistic antitumor effect (Abstract).
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.
Citation of Relevant Prior Art
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nemerow et al (U.S. 2002/0193327) is considered relevant prior art for having claimed a method of treating retinoblastoma (claims 20 and 22) in a subject, wherein the subject is human (claim 23), the method comprising the step of administering via intraocular or intravitreal injection (claims 12-13) an adenovirus vector (claims 10 14-17) encoding a therapeutic gene product (claim 19).
McVey et al (U.S. 2005/0220768; of record) is considered relevant prior art for having disclosed methods of delivering a gene product expression vector to the eye of a subject (claims 1, 30, and 33), and methods of treating an ocular-related disorder in a subject comprising the administration of a gene product expression vector to the eye of a subject (claim 15), the methods comprising the step of also administering hyaluronidase to the eye (claims 1, 15, and 30), wherein the gene product expression vector is an adenoviral vector (claims 2-5, 7, 9-11, 13, 16-19, 21, 23-25, 27, 31-35, 37, and 40-41), and wherein the ocular disorder includes retinal tumors and retinal degenerative disease (claim 29). McVey et al disclosed, for example, the hyaluronidase is useful to effect breakdown of blood and blood proteins in the vitreous of the eye [0087] or upregulate transcription of the thus-delivered gene product [0103], whereby hyaluronidase therapeutic products for the eye are commercially available (e.g. VitraseTM) [0087].
Abdulrazik (U.S. 2007/0117750; of record) is considered relevant prior art for having disclosed the use of hyaluronidase (claim 17) in methods of enhancing drug penetration to ocular tissues (claim 1), wherein the drug penetration enhancer(s) are administered to the eye via, e.g. intravitreal routes (claim 8).
Bookbinder et al (U.S. Patent 7,767,429; of record) is considered relevant prior art for having disclosed pharmaceutical compositions comprising hyaluronidase (e.g. claims 1 and 5) being formulated for intravitreal administration (e.g. claim 27), whereby injection into the eye is useful for the treatment of glaucoma (reduce intraocular pressure), dissolve vitreous aggregates, clear vitreous hemorrhage, and treatment of macular degeneration (e.g. col. 8, lines 50-59).
It is unclear what is so unpredictable about using an oncolytic adenovirus expressing hyaluronidase to be effective in treating retinoblastoma when, prior to the effective filing date of the instantly claimed invention, the effects of administering hyaluronidase in the hyaluronan-rich environment of the eye was previously recognized and suggested in therapeutic methods, including methods of treating retinal tumors, delivering adenoviral expression vectors into the eye, and enhancing drug penetration in the eye.
McFadden et al (U.S. 2006/0263333; of record) is considered relevant prior art for having disclosed the use of oncolytic viruses (e.g., [0058]) to treat CNS tumors, including retinoblastoma and pinealoma (syn. trilateral retinoblastoma) (e.g. [0080]).
Ganesh et al (Cancer Research 67(9): 4399-4407, 2007; of record) is considered relevant prior art for having taught wherein oncolytic adenoviruses expressing relaxin demonstrated significantly enhanced transduction and increased viral spread throughout tumor when compared with non-relaxin-expressing Ad5-based viruses (Abstract).
Ganesh et al (Clin. Cancer Res. 14(12): 3933-3941, 2008; co-authors to Ganesh (2007), above; of record in IDS) is considered relevant prior art for having taught wherein rHuPH20 improves viral spread and replication in the tumor underlie the enhanced potency of oncolytic adenovirus (pg 3937, col. 2).
Thus, even though relaxin and hyaluronidase are different proteins, those of ordinary skill in the art previously recognized that both relaxin and hyaluronidase are each capable of improving the spread of oncolytic adenoviral vectors.
Song et al (Invest. Ophthalmol. & Vis. Sci. 51(5): 2626-2635, 2010; of record) is considered relevant prior art for having taught a method of treating retinoblastoma in a subject, the method comprising the step of administering an oncolytic adenovirus to the subject, thereby treating said subject. Song et al used a mouse xenograft model of HXO-RB44 retinoblastoma cells (pg 2627, col. 1, Methods), said HXO-RB44 cells being art-recognized chemoresistant retinoblastoma cells (Wang et al, 2015). Song et al taught that the oncolytic adenovirus is able to kill the HXO-RB44 cells in both in vitro (pg 2629, col. 1, “Cytotoxicity of H101 In Vitro”) and in vivo assays (pg 2630, col. 2, “Inhibition of Tumor Growth and Prolongation of Mouse Survival In Vivo by Treatment with H101”; Figure 7).
Wang et al (Int. J. Clin. Exp. Pathol. 8(3): 2525-2534, March 1, 2015; of record) is considered relevant prior art for having taught that retinoblastoma cell line HXO-RB44 (taught by Song et al (2010, 2012) is an art-recognized chemoresistant cell line
Conclusion
9. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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