DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12 August 2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-3, 7, and 10-20 in the reply filed on 14 October 2025 was previously acknowledged.
Claims 4-6 and 8-9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 14 October 2025.
Claim Status
Claims 4-6 and 8-9 have been withdrawn, claim 17 has been canceled, claims 1-5, 7, 11, 14-16, 18-19 have been amended, and claims 1-3, 7, 10-16, and 18-20 have been considered on their merits.
Withdrawn Rejections
The claim rejections under 35 U.S.C. 103 have been withdrawn due to Applicant’s amendments to the claims. However, upon further consideration, new grounds of rejection are set forth below.
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.
Claims 1-3, 7, 10-16, and 18-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for administering an anti-cancer drug to a patient in need thereof, comprising reducing uptake or accumulation of the anti-cancer drug in nontumor major organ tissue by administering a pre-treatment composition comprising an IFN-λ and a specific lipoplex composition in specific nontumor major organ tissues to the patient about 30 minutes to about 72 hours prior to administering the anti-cancer drug; and subsequently administering a therapeutically effective amount of an anti-cancer drug to the subject, wherein the pre-treatment composition reduces uptake or accumulation of the anti-cancer drug in specific nontumor major organ tissue by at least 8% compared to uptake or accumulation of the anti-cancer drug in the absence of the pre-treatment composition, does not reasonably provide enablement for a method for administering an anti-cancer drug to a patient in need thereof, comprising a) reducing uptake or accumulation of the anti-cancer drug in any nontumor major organ tissue by administering any pre-treatment composition to the patient about 30 minutes to about 28 days prior to administering the anti-cancer drug; and b) subsequently administering a therapeutically effective amount of an anti-cancer drug to the subject, wherein the pre-treatment composition reduces uptake or accumulation of the anti-cancer drug in nontumor major organ tissue by at least 8% compared to uptake or accumulation of the anti-cancer drug in the absence of the pre-treatment composition.
This is a new rejection.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Breadth of the claims
Claim 1 discloses a method for administering an anti-cancer drug to a patient in need thereof, comprising a) reducing uptake or accumulation of the anti-cancer drug in nontumor major organ tissue by administering a pre-treatment composition to the patient about 30 minutes to about 28 days prior to administering the anti-cancer drug; and b) subsequently administering a therapeutically effective amount of an anti-cancer drug to the subject, wherein the pre-treatment composition reduces uptake or accumulation of the anti-cancer drug in nontumor major organ tissue by at least 8% compared to uptake or accumulation of the anti-cancer drug in the absence of the pre-treatment composition.
The scope of claim 1 is broad to include any pre-treatment composition, any anti-cancer drug, and any nontumor major organ tissue.
Claim 2 further limits the pre-treatment composition to include a composition comprising any nucleic acid and any nanoparticle mimic, any IFN-λ, or any combination thereof.
Claim 3 further limits the nanoparticle mimic to any lipoplex composition comprising a lipid nanoparticle (NP).
Claim 7 further limits the composition of the lipid NP.
Claim 10 discloses the type of nucleic acids.
Claim 11 limits the method of administration to parenterally.
Claim 12 further limits the composition of the anti-cancer agent.
Claim 13 limits the scope of the tumor to a solid tumor.
Claims 14-16 limit the scope of the number of times and the timing of the pre-treatment composition administration.
Claim 18 further limits the intended duration of the pre-treatment composition has on the uptake of an anti-cancer drug in nontumor major organ tissues.
Claim 19 is an independent claim directed to a method for selectively reducing uptake or off-target accumulation of an agent in major organ nontumor tissue of a subject comprising administering to said subject an effective amount of a pre-treatment composition about 30 minutes to about 28 days prior to administering the agent, wherein the pre-treatment composition reduces uptake of the agent by at least 8% compared to uptake without said pre-treatment composition, wherein the pre-treatment composition is a composition comprising IFN-λ, is a composition comprising a nucleic acid and a nanoparticle mimic, an IFN- λ or a combination thereof.
The scope of claim 19 is broad to include reducing uptake or off-target accumulation of any agent in any major organ nontumor tissue wherein the composition comprises any nucleic acid and any nanoparticle mimic and/or any IFN- λ.
Claim 20 limits the composition of the nanoparticle mimic to a lipoplex composition comprising a lipid NP.
A method of administering any pre-treatment composition, any anti-cancer drug, and reducing uptake in any nontumor major organ tissue would be highly unpredictable as the instant disclosure was found to be successful with specific pre-treatment compositions in specific major organ tissues.
Nature of the invention
The nature of the invention is a method of administering a pre-treating composition to reduce the uptake of anti-cancer drugs in nontumor major organ tissue. However, the disclosed methods in the specification are specific to administering a specific lipoplex and/or IFN- λ composition to a subject which reduces uptake of an anti-cancer drug in a select group of nontumor major organ tissues.
State of the prior art
The state of the art in the field of methods for administering cancer pre-treatments to reduce the uptake of anti-cancer drugs is relatively low. However, there is substantial information pertaining to the effects of IFN- λ as it relates to cancer treatments and the effects on epithelial cells.
Odendall (J Immunol. 01 November 2017; 199(9): 3270–3279, of record) teaches recombinant IFN-λs enhanced epithelial barriers in vitro (Abstract). Odendall teaches functionally, IFN-λs are particularly important at barrier surfaces, which are locations rich in epithelial cells that express high levels of IFN-λ receptors (p. 1, Introduction). Odendall teaches recombinant IFN-λs increased the barrier functions of polarized human intestinal epithelial cell lines (p. 3, Introduction). Odendall teaches IFN-λs appear to play an important role of reinforcing epithelial and endothelial barriers (p. 11, Discussion).
Lazear (Immunity 43, 21 July 2015, IDS ref., of record) teaches a specialized role for IFN-λ in providing antiviral activity at anatomic barriers, including epithelial surfaces and the blood-brain barrier (BBB) without activating a systemic pro-inflammatory immune response (p. 15, Introduction). While Lazear describes this effect as antiviral, the effect remains, IFN-λ provides protection at anatomic barriers, such as those found in major organ tissues. Lazear teaches epithelial cells are the predominant IFN-λ-responsive cell type in the gastrointestinal tract (p. 19, IFN-λ in the Gastrointestinal Tract). Lazear teaches IFN-λ stimulation at the BBB creates endothelial tightening (p. 21, IFN-λ at the BBB and Fig. 2D), and the BBB protects the brain, a major organ.
Yan (Biomedicine & Pharmacotherapy 88, published 2017, of record) teaches use of IFN-λ3 as an adjuvant treatment with sorafenib in hepatocellular carcinoma (HCC) (Abstract). Yan teaches treatment with a combination of IFN-λ3 and sorafenib suppresses the viability of HepG2 and SMMC7721 liver cancer cell lines more than treatment with either alone (Abstract). Yan teaches Sorafenib is a small molecule multikinase inhibitor that is active in several cancer cell lines through its ability to inhibit cell proliferation, induce cell apoptosis, and suppress angiogenesis (p. 395, Introduction). Yan teaches sorafenib has gained acceptance as a first-line treatment for advanced and metastatic HCC (p. 396, 1st column). Yan teaches treatment with a combination of sorafenib and IFN-λ3 had a synergistic effect on tumor cell growth suppression (p. 398, Results). Thus, demonstrating IFN-λ was known in the art to be used in cancer therapy.
Post art El-Zahaby (AAPS PharmSciTech (2024) 25:131) teaches lipoplex structure, preparation and role in managing different diseases (Abstract). El-Zahaby teaches specific aspects such as the ability to control their properties on both lengths are obligated (p. 131). El-Zahaby teaches other features include their size and surface charge, that are used to evaluate their stability in serum, wherein, in vivo circulation time and their proper interactions with cells are also required (p. 131). El-Zahaby teaches thermodynamics governs the local structure of lipoplexes which is illustrated by a phase diagram that establishes relationships between the properties of the lipid(s), composition, and nucleic acid content to the structure of the assembly (p. 131). El-Zahaby teaches lipid-based vectors are promising tools for drug delivery, but their potential toxicity and immunogenicity are challenging as different lipid components can exhibit varying degrees of cytotoxicity (p. 131). El-Zahaby teaches cationic lipids, commonly used for nucleic acid delivery due to their ability to form complexes with negatively charged nucleic acids, can induce cytotoxicity through interactions with cellular membranes and disruption of membrane integrity (p. 131). Thus, demonstrating that lipoplex functions would be dependent on the structure and chemical composition of said lipoplex which would lead one of ordinary skill to find the function of any lipoplex to be unpredictable.
Level of predictability in the art
The art teaches IFN-λ was known in the prior art to be utilized in cancer treatments as well as the effects on epithelial tight junctions, making IFN-λ a predictable choice for the utilization in methods of administering anti-cancer treatment. The nature of lipoplexes makes the utilization of these in anti-cancer therapies as a pretreatment composition unpredictable as the effectiveness of said lipoplexes are dependent on thermodynamics based on their size, surface charge, and composition. Thus, suggesting the utilization of any lipoplex in this method would be unpredictable.
Direction provided by the Inventors/Working examples
The instant specification discloses, in Example 7 and Fig. 12, a significant reduction in major organ tissue uptake following lipoplex administration but only in liver, spleen. Fig 13 compares organ uptake compared to tumor uptake and shows a significant difference in the liver, spleen, lung, brain, heart, and kidney. Fig. 14 shows the efficiency of a liposome comprising DNA only being significant in the spleen. From the disclosure found in the examples of the specification it appears as though only administering the specific lipoplex creates any type of significant reduction in uptake in most nontumor organ tissues. Furthermore, the instant specification discloses the tightening effect of administering the lipoplex composition was only measured up to 72 hours, thus making the claim to 28 days highly unpredictable. The specification at paragraph [0219] demonstrates that IFN-λ pretreatment significantly reduces Doxil accumulation in the skin, kidney, lungs, and heart when compared to mice pretreated with PBS wherein the reduction in Doxil accumulation for other major organs, such as liver and spleen were not found to be significant. Thus, demonstrating not efficacious for any nontumor organ tissue. The disclosure of the specification makes the method disclosed in claim 1 of reducing uptake or accumulation of the anti-cancer drug in any nontumor major organ tissue by administering any pre-treatment composition to a patient about 30 minutes to about 28 days prior to administering the anti-cancer drug highly unpredictable.
Therefore, the instant specification provides examples of successfully reduction in accumulation of an anti-cancer drug in certain nontumor major organ tissues with specified pre-treatment compositions, however, no working examples were provided demonstrating this effect in all major organ tissues nor with any pre-treatment composition. Based on the information provided by the art, one of ordinary skill in the art would have predicted the effectiveness of the administration of IFN-λ, however, the effectiveness of any nucleic acid and a nanoparticle mimic, such as a lipoplex, would be unpredictable due to the complex thermodynamic nature of lipoplex compositions and the potential cytotoxic nature.
Accordingly, claim 1 and 19 fail to satisfy the enablement requirement for the full scope of the claims. Claims 2-3, 7, 10-16, and 18-20 are included in the rejection because they ultimately depend from claim 1 and claim 19 and do not remedy the issue.
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.
Claims 1-3, 7, 10-16, and 18-20 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.
Regarding claims 1 and 19, it is not clear if the scope of the reduction in uptake or off-target accumulation in “nontumor major organ tissue” (claim 1) and “major organ nontumor tissue” (claim 19) is required to effect all nontumor major organ tissues or the effect is required for only one major organ tissue. Therefore, the scope of the claim is unclear as to what is included or excluded for the claimed method. The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973).
Claim 19 states, in the last three lines of the claim, “wherein the pre-treatment composition is a composition comprising interferon λ (IFN- λ), is a composition comprising a nucleic acid and a nanoparticle mimic, an interferon λ (IFN- λ) or a combination thereof”, which appears to contain a typographical error. This wherein clause makes the scope of the claim unclear as to what is included or excluded for the claimed method as IFN- λ is listed twice. The language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds". See, e.g., the following decisions: In re Hammack, 427 F 2d. 1378, 1382, 166 USPQ 204, 208 (CCPA 1970); In re Venezia 530 F 2d. 956, 958, 189 USPQ 149, 151 (CCPA 1976); In re Goffe, 526 F 2d. 1393, 1397, 188 USPQ 131, 135 (CCPA 1975); In re Watson, 517 F 2d. 465, 477, 186 USPQ 11, 20 (CCPA 1975); In re Knowlton 481 F 2d. 1357, 1366, 178 USPQ 486, 492 (CCPA 1973).
For the purpose of compact prosecution, the claim is interpreted as the “pre-treatment composition” is a composition minimally comprising (i) a nucleic acid and a nanoparticle mimic, (ii) an interferon λ (IFN- λ), or a combination both (i) and (ii).
The dependent claims are included in the rejection because they do not remedy the issues.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (Biomedicine & Pharmacotherapy 88, published 2017, of record) as evidenced by Lazear et al. (Immunity 43, 21 July 2015, IDS ref., of record) and Odendall et al. (J Immunol. 01 November 2017; 199(9): 3270–3279, of record).
This rejection is substantially similar to the rejection of record; however, the newly added limitations necessitated a new rejection, thus, this is a new rejection necessitated by Applicant’s amendment to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 1, Yan teaches use of IFN-λ3 as an adjuvant treatment with sorafenib in hepatocellular carcinoma (HCC) (Abstract). Yan teaches treatment with a combination of IFN-λ3 and sorafenib suppresses the viability of HepG2 and SMMC7721 liver cancer cell lines more than treatment with either alone (Abstract). Yan teaches Sorafenib is a small molecule multikinase inhibitor that is active in several cancer cell lines through its ability to inhibit cell proliferation, induce cell apoptosis, and suppress angiogenesis (p. 395, Introduction). Yan teaches sorafenib has gained acceptance as a first-line treatment for advanced and metastatic HCC (p. 396, 1st column). Yan teaches treatment with a combination of sorafenib and IFN-λ3 had a synergistic effect on tumor cell growth suppression (p. 398, Results). Yan teaches IFN-λ3 up-regulate IFN stimulated genes (ISGs) by binding to heterodimeric class II cytokine receptors through the Janus kinase/signal transducer and activator of transcription (Jak-STAT) intracellular signaling pathway (p. 399). Yan teaches non-tumoral hepatocytes lack sensitive response to sorafenib and IFN-λ3 co-treatment (p. 400). Yan teaches treatment with a combination of IFN-λ3 and sorafenib induced production of ROS in HepG2 and SMMC7721 liver cancer cell lines (Fig. 5).
Yan does not specifically point to IFN-λ3 reducing uptake or accumulation of anti-cancer drugs in nontumor major organ tissues, however, the effect of INF- λ3 on barrier cells of major organ tissues was known in the art, as evidenced by Lazear and Odendall.
Lazear teaches IFN-λ not only stimulates expression of antiviral interferon-stimulated genes (ISGs) preferentially in cells of epithelial origin, but additionally there have been additional mechanisms in other cell types and tissues (Abstract). Lazear teaches a specialized role for IFN-λ in providing antiviral activity at anatomic barriers, including epithelial surfaces and the blood-brain barrier (BBB) without activating a systemic pro-inflammatory immune response (p. 15, Introduction). While Lazear describes this effect as antiviral, the affect remains, IFN-λ provides protection at anatomic barriers, such as those found in major organ tissues. Lazear teaches epithelial cells are the predominant IFN-λ-responsive cell type in the gastrointestinal tract (p. 19, IFN-λ in the Gastrointestinal Tract). Lazear teaches IFN-λ stimulation at the BBB creates endothelial tightening (p. 21, IFN-λ at the BBB and Fig. 2D), and the BBB protects the brain, a major organ. Lazear teaches the tightening of the endothelial cells of the BBB restricts viral neuroinvasion and reduces viral titers of the CNS (p. 21, IFN-λ at the BBB). Additionally, Lazear teaches IFN-λ could have a prominent barrier effect in epithelial tissues where IFNLR expression is higher, such as in the skin where the IFN-λ receptor, IFNLR, is expressed predominantly on keratinocytes (p. 21, IFN-λ and Autoimmunity). Lazear teaches since IFN-λ can alter tumorigenesis directly and indirectly, it might have utility as an adjunctive anti-cancer therapy (p. 22, IFN-λ in Cancer).
Odendall teaches recombinant IFN-λs enhanced epithelial barriers in vitro (Abstract). Odendall teaches functionally, IFN-λs are particularly important at barrier surfaces, which are locations rich in epithelial cells that express high levels of IFN-λ receptors (p. 1, Introduction). Odendall teaches recombinant IFN-λs increased the barrier functions of polarized human intestinal epithelial cell lines (p. 3, Introduction). Odendall teaches IFN-λs appear to play an important role of reinforcing epithelial and endothelial barriers (p. 11, Discussion).
Yan as evidenced by Lazear and Odendall suggest administering of a composition comprising IFN-λ reduces uptake or accumulation of anti-cancer drugs in nontumor major organ tissues and Yan teaches administering an anti-cancer agent; however, is silent to the order and timing in which the pre-treatment composition and anti-cancer agent are administered.
However, the order and timing of administration of the pre-treatment composition to reduce the uptake or accumulation in nontumor major organ tissues and administering an anti-cancer agent would have been readily optimizable by one having ordinary skill in the art by routine experimentation in order to achieve optimal results. MPEP2144.04(IV)(C). Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Additionally, MPEP § 2112 states "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id.
Since the effects of both IFN-λ and sorafenib were known in the art, there would have been a reasonable expectation of success in administering the IFN-λ prior to the sorafenib because Yan proposed adding IFN-λ3 to traditional sorafenib therapy may provide increased benefit to patients with HCC (p. 396, 1st column) and Lazear teaches since IFN-λ can alter tumorigenesis directly and indirectly, therefore may have utility as an adjunctive anti-cancer therapy (p. 22, IFN-λ in Cancer). There being a finite order of administration; IFN-λ first, sorafenib first, or IFN-λ and sorafenib simultaneously; one would be able to discover the optimal order to achieve ideal results via routine experimentation.
Regarding the limitation directed to wherein the pre-treatment composition reduces uptake or accumulation of the anti-cancer agent in nontumor major organ tissue by at least 8% compared to uptake or accumulation of the anti-cancer agent in the absence of pre-dosing.”, in the last four lines of the claim, are considered intended results. MPEP 2111.04(I) states, “The court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. Therefore, because the method steps are recited by the prior art, the intended results would necessarily occur.
Regarding claim 18, the limitation directed to wherein the administration of the pre-treatment composition reduces uptake or accumulation of an anti-cancer drug in nontumor major organ tissues for a duration of from about 3 hours to about 28 days after administration of the pre-treatment composition, are considered intended results. MPEP 2111.04(I) states, “The court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. Therefore, because the method steps are recited by the prior art, the intended results would necessarily occur.
Regarding claim 19, Yan as evidenced by Lazear and Odendall suggest the administration of IFN-λ3 (a pre-treatment composition), which was known to provide tightening of epithelial junctions, thus necessarily preventing uptake of an agent (sorafenib) in nontumor major organ tissues, see the rejections of claims 1 and 18 above.
Regarding the limitation directed to wherein the pre-treatment composition reduces uptake of the agent by at least 8% compared to uptake without said pre-treatment composition, are considered intended results. MPEP 2111.04(I) states, “The court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. Therefore, because the method steps are recited by the prior art, the intended results would necessarily occur.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see Remarks, filed 12 August 2026, with respect to the rejections of claims 1-3, 7, and 10-20 under 35 U.S.C. § 103 have been fully considered and are persuasive to the extent that the rejections of record did not address the new limitations found in amended claims. It is maintained that the teachings of Yan as evidenced by Lazear and Odendall suggest the teachings of the amended claims.
In response to applicant's argument that prior art does not teach the method which includes a pre-treatment composition, specifically the administration of IFN-λ, about 30 minutes to about 28 days prior to administration of an anti-cancer drug, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In response to Applicant’s assertion of unexpected results on pages 9 of the remarks, although Applicant argues unexpected results, the claims are not commensurate in scope with the examples found in the instant specification. MPEP 716.02(d) states that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983). In this case, the claims are directed to administering any composition as a pretreatment and expecting the result of a reduction in uptake of anti-cancer drugs in any nontumor major organ tissue. Furthermore, there is no data from the instant disclosure to compare the effects of simultaneous administration of the pre-treatment and the anti-cancer drug with that of a staggered administration. Therefore, without evidence to the contrary, there is nothing to suggest the result would have been significantly different.
It has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this instance Yan is in the field of the inventor’s endeavor and are reasonably pertinent to the particular problem with which the inventor was concerned.
Furthermore, MPEP 716.02(b) states the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
Additionally, regarding the assertion that an alteration in the order of administration resulted in loss of functionality. This argument is merely the argument of counsel and is unsupported by evidence or declarations of those skilled in the art. Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See M.P.E.P. § 2129 and § 2144.03 for a discussion of admissions as prior art. Counsel's arguments cannot take the place of objective evidence. In re Schulze, 145 USPQ 716 (CCPA 1965); In re Cole, 140 USPQ 230 (CCPA 1964); and especially In re Langer, 183 USPQ 288 (CCPA 1974). See M.P.E.P. § 716.01(c) for examples of attorney statements that are not evidence and that must be supported by an appropriate affidavit or declaration.
Regarding the argument directed to Yan teaching IFN-λ as an adjuvant treatment, an adjuvant therapy is not required to be administered simultaneously; adjuvant is defined as enhancing the effectiveness of medical treatment.
In response to applicant's argument that the references teaches away from the invention and fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., non-tumor cells do not respond to IFN- λ) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding the argument directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the reference utilized was shown to not be deficient. Additionally, Lazear and Odendall were used as evidentiary references which displayed the known function of IFN-λ as it relates to nontumor major organs.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Yan teaches both administration of both IFN-λ (a pre-treatment composition) and sorafenib (an anti-cancer agent). The evidentiary references were included in the rejection because they teach the inherent properties of the IFN-λ, which includes tightening of epithelial and endothelial junctions of nontumor major organ tissues, to include brain, intestine, and skin.
Claims 2-3, 10-14, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (Biomedicine & Pharmacotherapy 88, published 2017, of record) as evidenced by Lazear et al. (Immunity 43, 21 July 2015, IDS ref., of record) and Odendall et al. (J Immunol. 01 November 2017; 199(9): 3270–3279, of record) as applied to claims 1 and 18-19 above, and further in view of Liang et al. (Oncotarget, Vol. 7, No. 32, published 11 July 2016, of record).
This rejection is substantially similar to the rejection of record; however, the newly added limitations necessitated a new rejection, thus, this is a new rejection necessitated by Applicant’s amendment to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claims 2 and 10, the composition of Yan as evidenced by Lazear and Odendall reads as a composition comprising IFN-λ.
Yan as evidenced by Lazear and Odendall do not teach wherein the composition comprises a nucleic acid and a nanoparticle mimic (claim 2), wherein the nucleic acid is double stranded DNA (claim 10).
Liang teaches lipoplex delivery of a recombinant cytokine for immunotherapy for colon cancer (Abstract). Liang teaches DNA-liposome complexes (lipoplexes) are formed by electrostatic interaction between DNA and two or more cationic liposomes resulting in a DNA-liposome complex (p. 52208, Results). Liang teaches the plasmid DNA (double stranded DNA) (claim 10) encoding IL-15 in the folate-modified PEGylation liposome (F-PLP/IL15) provided increased stability compared to naked pIL15 when exposed to DNase I (p. 52208, Results).
It would have been obvious to one of ordinary skill in the art to deliver the IFN-λ of Yan with the lipoplex of Liang with a reasonable expectation of success because Liang teaches lipoplexes comprising cytokines can be used in a method of treating cancer and the use of the lipoplexes taught by Liang provides increased stability of the cytokine compared to naked pIL15. One would be motivated to deliver the IFN-λ of Yan with the lipoplex of Liang because Liang teaches lipoplexes can be used for delivering cytokines as part of cancer immunotherapy and Yan teaches IFN-λ can be utilized as part of cancer treatment. Additionally, lipoplexes offer simple production methods as well as the ability to be readily modified, such as PEGylation or targeting ligands as taught by Liang, which could result in increased circulation time or specific cell targeting.
Regarding claim 3, Liang teaches the DNA-liposome complexes have a size of 250-300 nm, therefore, the liposome reads as comprising a lipid nanoparticle (p. 52208, Results). According to the instant specification at para. [0108], which identifies a lipid nanoparticle having a diameter from about 10 nm up to greater than 1000 nm.
Regarding claim 11, Yan teaches in a tumorigenicity assay in a mouse model, IFN-λ3 was administered via tail vein injection (p. 397, section 2.13). Tail vein injection reads as administered parenterally.
Regarding claim 12, Yan teaches the anti-cancer agent is sorafenib, a small molecule multikinase inhibitor that is active in several cancer cell lines through its ability to inhibit cell proliferation, induce cell apoptosis, and suppress angiogenesis (p. 395, Introduction). Sorafenib reads as an anti-cancer agent which lacks nucleic acids. The limitations of claim 12 are listed in the alternative, therefore, sorafenib reads on the limitations of the claim.
Regarding claim 13, Yan teaches a tumorigenicity assay in a mouse model utilizing tumors formed by SMMC7721 cells (p. 397, section 2.13). Yan teaches treatment of human hepatocellular carcinoma (HHC) cells; HepG2, SMMC7721, SK-Hep-1, and BEL-7402 (p. 396, section 2.3). HHC cells are solid tumor forming cells.
Regarding claims 14 and 16, Yan teaches teach IFN-λ3 is injected into the tail vein every day (reads as repeated about 24 hours) (claim 16) for 28 days and the anti-cancer agent is administered every day for 28 days via intragastric administration (p. 397, section 2.13). Claim 14 is interpreted as requiring the administration of the pre-treatment composition is repeated prior to each dose of the anti-cancer agent.
Regarding the order in which the pre-treatment composition and anti-cancer agent are administered, as discussed in the rejection of claim 1, Yan does not indicate the order in which the composition and anti-cancer agent are administered, however, the order in which the pre-treatment composition and the anti-cancer agent would have been readily optimizable by one having ordinary skill in the art by routine experimentation in order to achieve optimal results. The order of administration of the composition to reduce uptake or accumulation of the anti-cancer drug in nontumor major organ tissues and administering an anti-cancer agent would have been readily optimizable by one having ordinary skill in the art by routine experimentation in order to achieve optimal results. MPEP2144.04(IV)(C). Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Regarding claim 20, Yan as evidenced by Lazear and Odendall do not teach wherein the pre-treatment composition comprising a nucleic acid and a nanoparticle mimic, wherein the nanoparticle mimic is a lipoplex comprising a lipid nanoparticle (NP).
However, Liang teaches the DNA-liposome complexes have a size of 250-300 nm, therefore, the liposome reads as comprising a lipid nanoparticle (p. 52208, Results). According to the instant specification at para. [0108], which identifies a lipid nanoparticle having a diameter from about 10 nm up to greater than 1000 nm. Liang teaches the alpha isoform of the folate receptor (FRα) is associated with tumor cell proliferation, migration, and invasion, with FRα overexpressed in approximately 30-40% of human colorectal carcinoma tissues (p. 52208, Introduction). Liang teaches FRα-targeted non-viral vectors potentially having a place in colon cancer immunogene therapy (p. 52208, Introduction). Liang teaches the lipoplex comprising the plasmid DNA encoding IL-15 in the folate-modified PEGylation liposome (F-PLP/IL15) (a target specific lipoplex) provided increased stability compared to naked pIL15 when exposed to DNase I (p. 52208, Results).
Therefore, it would have been obvious to one of ordinary skill in the art to deliver the IFN-λ of Yan with the targeted lipoplex of Liang with a reasonable expectation of success because Liang teach targeted lipoplexes comprising cytokines can be used in a method of treating cancer and the use of the lipoplexes taught by Liang provide increased stability of the cytokine compared to naked pIL15 and Yan teaches IFN-λ3 was shown to provide the tightening of epithelial junctions. One would be motivated to deliver the IFN-λ of Yan with the targeted lipoplex of Liang because Liang teaches lipoplexes can be used for delivering cytokines to a selected group of cells via the ability to design a lipoplex with a specific targeting moiety and Yan teaches IFN-λ can be utilized as part of cancer treatment, which would provide the tightening of epithelial junctions. Additionally, lipoplexes offer simple production methods as well as the ability to be readily modified, such as PEGylation or targeting ligands as taught by Liang, which could result in increased circulation time or specific cell targeting.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant argues Liang do not cure the deficiencies of Yan, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant argues the goal of the method in the claims is for reducing uptake in non-tumor cells. As discussed in the above rejections, administration of IFN-λ would necessarily result in the reduction of uptake in nontumor major organ tissues of an anti-cancer agent/agent. The focus of Liang does not detract from the results which would necessarily occur when administration of IFN-λ. It has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this instance Yan and Liang are in the field of the inventor’s endeavor and are reasonably pertinent to the particular problem with which the inventor was concerned.
Regarding points 2 and 3 in the arguments directed to Liang, since the language of the claim utilized the open language “comprising” regarding the pre-treatment composition, this composition is not limited to any particular type of nucleic acid, therefore, the teachings of Liang read as a composition comprising a nucleic acid and a nanoparticle mimic.
Claims 7 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (Biomedicine & Pharmacotherapy 88, published 2017, of record) as evidenced by Lazear et al. (Immunity 43, 21 July 2015, IDS ref., of record) and Odendall et al. (J Immunol. 01 November 2017; 199(9): 3270–3279, of record) in view of Liang et al. (Oncotarget, Vol. 7, No. 32, published 11 July 2016, of record), as applied to claims 2-3, 10-14, 16, and 20 above, and further in view of Betker et al. (Journal of Pharmaceutical Sciences 106 (2017), published 22 November 2016, IDS ref., of record).
This rejection is substantially similar to the rejection of record; however, the newly added limitations necessitated a new rejection, thus, this is a new rejection necessitated by Applicant’s amendment to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 7, Liang teaches DOTAP, Cholesterol, and F-PEG-suc-Chol were used to prepare the folate-modified PEGylation liposome (F-PLP) (p. 52214, 1st column).
Yan as evidenced by Lazear and Odendall in view of Liang et al. do not teach wherein the lipid NP is formulated with asymmetric phospholipid: structural lipid: symmetric phospholipid.
However, Betker teaches sphingosine (asymmetric phospholipid), 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) (symmetric phospholipid), and cholesterol (structural lipid) where used to prepare liposomes at a 3:2:5 mole ratio (p. 873, Materials and Methods). Betker teaches these liposomes were mixed with a modified pSelect-LucSh plasmid encoding luciferase, thereby, forming the lipoplex (p. 873, Materials and Methods). Betker teaches their lipoplexes composed of naturally occurring lipids (i.e., phosphatidylcholine, cholesterol, sphingosine) greatly reduce their toxicity and potential immunogenicity, as compared to other gene delivery vehicles (p. 877, Discussion). Betker teaches lipoplex formulations comprising DOTAP, PEG, or lipofectamine elicited elevation of a large number of cytokines and chemokines (Fig. 2 and Table 1), which can lead to IgM production and subsequent accelerated blood clearance (ABC) (p. 877, Discussion).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the lipoplex composition of Betker in the method of Yan in view of Liang with a reasonable expectation of success because Betker teaches their lipoplexes composed of naturally occurring lipids (i.e., phosphatidylcholine, cholesterol, sphingosine) greatly reduce their toxicity and potential immunogenicity, as compared to other gene delivery vehicles. One would be motivated to utilize the lipoplex of Betker in the method of Yan in view of Liang because Betker teaches the benefits of the lipoplex formulation comprising phosphatidylcholine, cholesterol, and sphingosine in comparison to the formulations comprising DOTAP and PEG as taught by Liang.
Regarding claim 15, Yan as evidenced by Lazear and Odendall in view of Liang do not teach administration of the pre-treatment composition is repeated four times prior to receiving a dose of the anti-cancer agent.
However, Betker teaches repeated administration of the lipoplex composition resulted in both plasmid levels (26-fold) and luciferase (plasmid) expression (10-fold) in the tumor are enhanced by more than 4-fold after the fourth dose as compared to that after a single administration (p. 876, Tumor Accumulation and Expression). Betker teaches repetitive administration enhances delivery is consistent with previous studies with both plasmid DNA and siRNA, suggesting delivery is increased beyond that seen after the initial administration, which was observed by successive injections 3 days apart (p. 878, 1st column). Betker teaches plasmid delivered to nontumor cells exhibit delayed expression due to reduced rates of cell division, and this contributes to the much larger enhancement of expression observed at later times, i.e., after 4 injections (p. 878, 2nd column).
Therefore, it would have been obvious to one of ordinary skill in the art to repeat administration of the pre-treatment composition four times prior to receiving a dose of the anti-cancer agent in the method of Yan as evidenced by Lazear and Odendall in view of Liang with a reasonable expectation of success because Betker teaches an enhancement of expression in nontumor cells following multiple injections. This finding suggests prolonged epithelial junction tightening in the nontumor cells surrounding the tumor cells. One would have been motivated to repeat administration of the pre-treatment composition up to four times prior to receiving a dose of the anti-cancer agent in the method of Yan as evidenced by Lazear and Odendall in view of Liang because enhanced expression, as indicated by Betker, of the lipoplex pre-treatment composition could lead to increased uptake or accumulation of the anti-cancer agent in the tumor tissue compared to nontumor tissue.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
There were no arguments specifically directed to these rejections, all traversals have been addressed above.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
