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 was filed in this application after a decision by the Patent Trial and Appeal Board, but before the filing of a Notice of Appeal to the Court of Appeals for the Federal Circuit or the commencement of a civil action. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on November 14, 2025 has been entered.
Detailed Action
This action is in response to the papers filed November 14, 2025.
Amendments
Applicant's amendments, filed November 14, 2025, is acknowledged. Applicant has cancelled Claims 2-3 and 11-21, amended Claim 1, and added new claims, Claim 22.
Claims 1, 4-10, and 22 are 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).
While 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 has not been provided.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
1. The prior rejection of Claim 21 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claim.
2. Claim 22 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites a method of treating retinoblastoma in a subject, the method comprising the step of administering by intravitreal injection a composition comprising at least 3x10^9 oncolytic adenovirus particles.
Claim 22 recites wherein the composition comprising at least 3x10^9 oncolytic adenovirus particles comprises a pharmaceutically acceptable excipient.
Claim 22 fails to further limit the method of Claim 1 because those of ordinary skill in the art have long-recognized that the administration of therapeutic agents, including oncolytic adenoviruses, necessarily requires the presence of a pharmaceutically acceptable excipient, including, but not limited to, at least the buffer into which the oncolytic adenoviruses are suspended.
Instant specification fails to disclose the administration the oncolytic adenoviruses in the absence of a pharmaceutically acceptable excipient.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
3. Claims 1 and 4-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a method of treating retinoblastoma in a subject, the method comprising the step of administering by intravitreal injection a composition comprising at least 3x10^9 oncolytic adenovirus particles.
Claim 22 recites wherein the composition comprising at least 3x10^9 oncolytic adenovirus particles comprises a pharmaceutically acceptable excipient.
Thus, the breadth of Claim 1 encompasses embodiments whereby the oncolytic adenoviruses are administered intravitreally in the absence of a pharmaceutically acceptable excipient.
Instant specification fails to disclose the administration the oncolytic adenoviruses in the absence of a pharmaceutically acceptable excipient.
The prior art does not teach administration the oncolytic adenoviruses in the absence of a pharmaceutically acceptable excipient.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
4. Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites wherein the retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment.
Claim 4 recites wherein the retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment is “refractory”.
Either this is an inherent property of (that naturally flows from) the retinoblastoma that is resistant to conventional chemotherapy and/or radiotherapy treatment of Claim 1, or it is not, and something of the retinoblastoma must change.
To the extent it is an inherent property of (that naturally flows from) the retinoblastoma that is resistant to conventional chemotherapy and/or radiotherapy treatment of Claim 1, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant claims, it is noted that the "wherein the retinoblastoma is refractory" clause does not recite any additional structure(s) but simply states a characterization the retinoblastoma that is resistant to conventional chemotherapy and/or radiotherapy treatment positively recited in Claim 1. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
Claim 4 “refractory” fails to further limit “retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment” because, by definition, “refractory” refers to a condition that is difficult to treat (syn. resistant to conventional chemotherapy and/or radiotherapy treatment).
Instant specification fails to disclose a first “retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment” that is not “refractory”, as opposed to a second “retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment” that is “refractory”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
5. Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites wherein the retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment.
Claim 4 recites wherein the retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment is “refractory”.
Either this is an inherent property of (that naturally flows from) the retinoblastoma that is resistant to conventional chemotherapy and/or radiotherapy treatment of Claim 1, or it is not, and something of the retinoblastoma must change.
Claim 1 denotes a genus of retinoblastomas that are resistant to conventional chemotherapy and/or radiotherapy treatment (Claim 1), but are not “refractory” (Claim 4).
To the extent it is not an inherent property of (that naturally flows from) the retinoblastoma that is resistant to conventional chemotherapy and/or radiotherapy treatment of Claim 1, then the claim is considered to lack adequate written description for failing to recite the structure(s) that is/are necessary and sufficient to cause the recited functional language “refractory”.
The limitation "wherein the retinoblastoma is refractory" merely states a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the retinoblastomas that is/are resistant to conventional chemotherapy and/or radiotherapy treatment recited in the independent claim.
Instant specification fails to disclose a first “retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment” that is not “refractory”, as opposed to a second “retinoblastoma is resistant to conventional chemotherapy and/or radiotherapy treatment” that is “refractory”.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
6. Claims 8-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites wherein the oncolytic adenovirus comprises replication machinery specific for tumor cells.
Claim 8 recites wherein 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. There is insufficient antecedent basis for this limitation in the claim because the independent claim does not require the retinoblastoma to comprise ‘both defective copies of the Rb1 gene’.
Rushlow et al (Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies, Lancet Oncology 14: 327-334, 2013) is considered relevant prior art for having taught that there are retinoblastomas that do not comprise RB1 mutations, e.g. MYCN oncogene amplification.
The instant claim as a whole does not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
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.
7. Claims 1, 4-10, and 22 are 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 (Absence of Systemic Immune Response to Adenovectors After Intraocular Administration to Children With Retinoblastoma, Molecular Therapy 18(10):1885-1890, 2010).
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, and with respect to Claim(s) 1 and 4, 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 limitation of administering at least (no upper limit) 3x10^9 oncolytic adenovirus particles,
Cascallo Piqueras et al disclosed administering to the tumor a pharmaceutical composition comprising a pharmaceutically acceptable carrier and:
at least 1x10^8 oncolytic adenovirus particles (e.g. pg 16, line 25);
at least 2x10^9 oncolytic adenovirus particles (e.g. pg 22, lines 23-28); and
at least 5x10^10 oncolytic adenovirus particles (e.g. pg 17, lines 9-10).
Ji et al taught administering via intraocular injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 1x10^7 oncolytic adenovirus particles (e.g. pg 195, col. 2, Treatment of RB).
Fueyo et al disclosed administering to the tumor a pharmaceutical composition comprising a pharmaceutically acceptable carrier and:
at least 1x10^8 oncolytic adenovirus particles (e.g. [0265]);
at least 3x10^10 oncolytic adenovirus particles (e.g. [0274]); and
at least 3x10^8, 1x10^9, 1x10^10, 3x10^10, or 1x10^11 oncolytic adenovirus particles (e.g. [0320, 331]).
Chen et al taught administering via intratumoral injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 1x10^9 oncolytic adenovirus particles (e.g. pg 4, 2.9 Animal Experiments).
Ildefonso et al is considered relevant prior art for having 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 (e.g. pg 1887, col. 2, last 2 lines).
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.
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).
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 administer to a subject by intravitreal injection to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 3x10^9 oncolytic adenovirus particles in a method of treating retinoblastoma with a reasonable expectation of success because:
i) 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 (e.g. pg 16, line 25; pg 22, lines 23-28; pg 17, lines 9-10);
ii) Fueyo et al and Chen et al taught/disclosed administering to the tumor a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 1x10^9, 1x10^10, 3x10^10, or 1x10^11 oncolytic adenovirus particles (e.g. Fueyo et al, [0265, 274, 320, 331]; Chen et al (pg 4, 2.9 Animal Experiments);
iii) Ji et al taught administering via intraocular injection a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least 1x10^7 oncolytic adenovirus particles in a mouse model method of treating retinoblastoma (e.g. pg 195, col. 2, Treatment of RB); and
iv) 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).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 5, Cascallo Piqueras et al 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 Claim 10, Cascallo Piqueras et al 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 Claim 6, Cascallo Piqueras et al disclosed wherein the hyaluronidase enzyme is the human hyaluronidase enzyme PH20 (pg 21, Example 4).
With respect to Claim 7, Cascallo Piqueras et al 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 Claims 8-9, Cascallo Piqueras et al 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).
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 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.
Conclusion
8. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638