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 .
Claim Status
Applicant’s preliminary amendments and remarks, filed 12/13/2023, are acknowledged.
Claims 1-19 are pending.
DETAILED ACTION
Election/Restrictions
Applicant’s election of immune checkpoint inhibitors or chemotherapeutic agents that target PD-L1 in the reply filed on 08/20/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 6-8 and 11-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/20/2026.
As such, claims 1-5, 9-10, and 14-19 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/25/2024 and 06/14/2024 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the figures are not provided in numerical order. Specifically, Fig, 10B is before Fig. 8. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Page 18, line 8: add space between “and/or” and “PD-L2”.
Page 34, line 1: “Miltenyi Biotech” should read “Miltenyi Biotec”.
Page 45, line 12: “compete” should read “complete”.
Appropriate correction is required.
The use of the term CyberKnife, TrueBeam, RapidArc, Gamma Knife, Bristol-Meyers Squibb, Roche, Genentech, Merck, AstraZeneca, MedImmune, Regeneron, Sanofi, Pfizer, GenBank, MedTec, Miltenyi Biotec, Invitrogen, EmboGold, and BioTek, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2-3 and 18-19 are objected to because of the following informalities:
Claims 2 and 3: “the subject’s HCC” should read “the HCC”.
Claims 18 and 19: add a comma (,) after “claim 1”.
Appropriate correction is required.
Claim Interpretation
Examiner acknowledges that the terms “treatment” and “treating” mean the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder (see page 24, lines 25-33).
Claim Rejections - 35 USC § 112(b)
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 1-5, 9-10, and 14-19 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 is drawn to “a method for treating a subject having hepatocellular carcinoma (HCC), the method comprising: (a) treating the subject with transarterial chemoembolization (TACE); (b) treating the subject with stereotactic body radiotherapy (SBRT); and (c) treating the subject with an immune checkpoint inhibitor, wherein the HCC comprises one or more tumors”; however the claim does not disclose any method steps that would actually result in “treating”. As stated above, the specification indicates that “treating” includes preventing a disease, but the claim language indicates that the subject already has HCC; therefore, it is unclear how these steps prevent HCC. As such, claim 1 and its dependent claims are rejected.
Claim Rejections - 35 USC § 112(a) Written Description
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 1-5, 9, and 14-19 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a method for treating a subject having hepatocellular carcinoma (HCC), the method comprising: (a) treating the subject with transarterial chemoembolization (TACE); (b) treating the subject with stereotactic body radiotherapy (SBRT); and (c) treating the subject with an immune checkpoint inhibitor, wherein the HCC comprises one or more tumors
Claim 2 is drawn to the method of claim 1, wherein the subject’s HCC is locally advanced.
Claim 3 is drawn to the method of claim 1, wherein the subject’s HCC is unresectable.
Claim 4 is drawn to the method of claim 1, wherein steps (a), (b), and (c) are performed sequentially in that order.
Claim 5 is drawn to the method of claim 1, wherein the immune checkpoint inhibitor targets programmed cell death ligand 1 (PD-L1).
Claim 9 is drawn to the method of claim 1, wherein the immune checkpoint inhibitor comprises a therapeutic antibody.
Claim 14 is drawn to the method of claim 1, wherein TACE comprises infusing a chemotherapeutic agent and an embolic particle into an artery supplying blood to one or more tumors of the HCC.
Claim 15 is drawn to the method of claim 14, wherein the chemotherapeutic agent and the embolic particle are infused together or separately.
Claim 16 is drawn to the method of claim 14, wherein the chemotherapeutic agent and the embolic particle are infused sequentially.
Claim 17 is drawn to the method of claim 14, wherein the embolic particle comprises a polyvinyl alcohol microsphere, superabsorbent microsphere, gelatin microsphere, or degradable starch microsphere.
Claim 18 is drawn to the method of claim 1, further comprising: resecting tumor tissue in the subject.
Claim 19 is drawn to the method of claim 1, further comprising: treating the subject with radiofrequency ablation.
The specification disclose that the terms “treatment” and “treating” mean the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder (see page 24, lines 25-33).
The specification disclose of a START-FIT triple therapy wherein the phase 2 trial investigated the activity and safety of sequential TACE, stereotactic body radiotherapy, and avelumab (an anti-PD-L1 drug) in patients with locally advanced HCC (see Example 1). Previous curative treatment (e.g., resection, radiofrequency ablation, percutaneous ethanol injection) was allowed (see page 28, lines 12-14). Patients who received any previous systemic therapy, TACE, radiotherapy to the liver, selective internal radiation, or those with liver volume minus the gross tumor volume of 700 mL or less were also excluded (see page 28, lines 19-21). All patients underwent a single treatment of conventional TACE within 28 days of study enrollment (see page 31, lines 7 and 8). At 28 days (plus or minus 3 days) after the completion of TACE, stereotactic body radiotherapy was delivered to all lesions (see page 31, lines 12-14). Patients then received the first dose of intravenous avelumab (10 mg/kg) 14 days (plus or minus 3 days) after the completion of stereotactic body radiotherapy; avelumab was then given every 2 weeks until the development of grade 3 or worse immune-related adverse events, disease progression, or withdrawal of consent (see pages 32-33).
33 patients were deemed eligible and enrolled in the study, wherein the patients received a median of eight cycles (IQR 4.5-12.0) of avelumab, and the median dose of stereotactic body radiotherapy was 30.0 Gy (range 30.0-35.0) in five fractions (see page 44, lines 1-3). Of the 18 (55%) of 33 patients who were deemed amenable to curative treatment after receiving the START-FIT regimen, eight were deemed amenable to resection, nine were deemed amenable to radiofrequency ablation, and one was deemed amendable to liver transplantation (see Table 6). Among all 33 patients, 14 (42%) had a complete response and four (12%) had curative treatment (two patients had resection and two patients had radiofrequency ablation); pathological review of the tumor specimens from the two patients who underwent resection showed a tumor necrosis rate that was 50% or higher (page 45, lines 3-9). The confirmed objective response rate was 67%; the complete response rate was 42%; the partial response was 24%; three (9%) patients had stable disease; and eight (24%) had progressive disease (see Table 9). The median time to treatment response was 3.8 months and the median duration of response was 20.2 months (see page 48, lines 1-2). Notably, all 14 patients who had a complete response had stopped avelumab upon achieving a complete response and the median number of cycles of avelumab received among patients who had a complete response was nine (see page 48, lines 2-6). 11 (79%) of 14 patients who had a complete response did not have disease progression at the time of data cutoff after a median follow-up of 17.2 months (see Fig. 2B). After a median follow-up of 17.2 months for the entire cohort, median progression-free survival was 20.7 months, median time to progression was 21.4 months, and median overall survival was 30.3 months (see Figs. 3A-3B). Patients who had a surge of exosomal PD-L1 at week 8 of avelumab (to 250 pg/mL or higher) had a better complete response rate than those who had exosomal PD-L1 concentrations lower than 250 pg/mL (see Figs. 10A-10B; Table 17). As such, sequential TACE, stereotactic body radiotherapy, followed by PD-L1 blockade in patients with locally advanced unresectable hepatocellular carcinoma resulted in 55% of patients becoming amenable to curative treatment, and 12% of patients undergoing curative treatment; moreover, 42% of patients who were enrolled in the trial had radiological complete response without surgery, and a 2-year overall survival rate of 92% (see page 61, lines 1-6). The objective response rate of 67% is superior compared with that of standalone systemic therapy (14-40%) and TACE (30%) in similar patient populations (see page 61, lines 8-10).
However, the specification fails to disclose Applicant’s possession of the claimed method of treating HCC patients. Specifically, the specification fails to disclose Applicant’s possession of the large genus of immune checkpoint inhibitors or chemotherapeutic agents as claimed. Further, the specification fails to disclose that Applicant was in possession of treating HCC with any PD-L1 inhibitor, excluding avelumab. Lastly, the specification fails to disclose steps (a), (b), and (c) being in any order as claimed.
Although the specification discloses treating locally advanced HCC comprising administering TACE, SBRT, and avelumab in sequential order, the claims are not limited to these inhibitors and are inclusive of any immune checkpoint inhibitor or chemotherapeutic agent to treat HCC in conjunction with TACE and SBRT. This indicates that there are hundreds, if not thousands, of possible inhibitors encompassed by the claims. Thus, the claims encompass a vast genus of inhibitor treatments that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of immune checkpoint inhibitors or chemotherapeutic agents because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Further, the specification fails to provide method steps that result in treating HCC patients. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecules function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/therapeutic agents and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of immune checkpoint inhibitors or chemotherapeutic agents . The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the immune checkpoint inhibitor to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of immune checkpoint inhibitors or chemotherapeutic agents , claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous immune checkpoint inhibitors or chemotherapeutic agents had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of immune checkpoint inhibitors or chemotherapeutic agents claimed only by a partial structure and functional characteristic(s). Thus, the immune checkpoint inhibitors or chemotherapeutic agents described by the instant claims encompasses an overly broad genus and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of immune checkpoint inhibitors or chemotherapeutic agents by the functions of treating HCC and targeting PD-L1. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless of whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed immune checkpoint inhibitors or chemotherapeutic agents , regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed immune checkpoint inhibitors or chemotherapeutic agents that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and therapeutic agents that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies/therapeutic agents or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed immune checkpoint inhibitors or chemotherapeutic agents that are proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges, it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed immune checkpoint inhibitors or chemotherapeutic agents could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Regarding immune checkpoint inhibitors or chemotherapeutic agents that are small molecules of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al. (Curr Med Chem. 2008;15(1):37-46), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind any particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al. (J. Med. Chem., 2014, 57 (12), pp 5023–5038), even when guided by structural data, developing selective structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular protein family member, or treat disease.
Regarding immune checkpoint inhibitors or chemotherapeutic agents that are nucleic acid-based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75–86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three-dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al. (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13).
Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA or proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all immune checkpoint inhibitors or chemotherapeutic agents .
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed immune checkpoint inhibitors or chemotherapeutic agents . Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of immune checkpoint inhibitors or chemotherapeutic agents as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Chiang et al
Claims 1-5, 9-10, and 14-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chiang et al (Journal of clinical oncology: official journal of the American Society of Clinical Oncology. , 2022, Vol.40, p.4091; published: 06/22/2022) as evidenced by Kotsifa et al (J. Pers. Med. 2022, 12, 436) and Lencioni et al (Semin Intervent Radiol 2013;30:3–11).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). This rejection under 35 U.S.C. 102(a)(1) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(1)(A); or (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(1)(B) if the same invention is not being claimed.
Chiang et al disclose of a study investigating the safety and efficacy of sequential TACE and SBRT followed by avelumab in patients with locally advanced HCC (see Background). Patients with locally advanced HCC not suitable for curative resections were eligible wherein all patients had HCC ≥ 5cm, tumor nodules ≤3, and child-Pugh A5-B7 liver function (see Methods). Patients underwent single episode of TACE followed by 5-fraction SBRT (28 days afterwards), followed by avelumab (10 mg/kg) 14 days afterwards and every 2 weeks thereafter (see Methods). The sample size assumed that around 20% patients amendable to surgery after experimental treatment compared to 5% of historical institutional results after TACE (see Methods). 33 patients were enrolled and the median sum of diameter of lesion(s) was 15.1 cm, and 21 (63.6%) had macrovascular invasion (see Results). After a median follow-up of 17.2 months, 3 (9.1%) patients had tumor downstaged with curative surgery done (see Results). The objective response was 62.5%, of whom 15 had complete response (CR) (43.8%) and 6 had partial response (18.7%) (see Results). The median overall survival (OS) and progression-free survival was 30.3 months and 20.7 months, respectively (see Results). All three patients with surgery done were alive at 2 years; for 15 patients had CR, the 2-year OS rate was 92.9% without surgery (see Results).
While Chiang et al does not explicitly disclose of the TACE comprising infusing a chemotherapeutic agent and an embolic particle as recited in instant claims 14-17, it was known in the art that the form of TACE used in HCC comprises using an embolic microsphere (e.g., degradable starch microsphere, gelatin, or non-resorbable) loaded with a chemotherapeutic agent as evidenced by Kotsifa et al and Lencioni et al.
As such, the teachings of Chiang et al anticipate the present invention.
START-FIT Protocol
Claims 1-5, 9-10, and 14-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by START-FIT v4 Study Protocol (uploaded online: 07/13/2022).
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). This rejection under 35 U.S.C. 102(a)(1) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(1)(A); or (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(1)(B) if the same invention is not being claimed.
The study protocol investigates the concept of combined TACE and SBRT followed by immune checkpoint inhibitor as a neo-adjuvant treatment in unresectable HCC patients (see entire document). Specifically, the study protocol assessed the safety and efficacy of the sequential administration of TACE and SBRT followed by avelumab in intermediate to advanced HCC patients (i.e., those diagnosed with unresectable HCC) (see Study Design and Inclusion Criteria). A total of 33 patients will be accrued to assess the potential benefit of combined TACE and SBRT followed by avelumab (see Study Participants). Protocol treatment must be within 28 days after study registration wherein TACE is first, followed by SBRT 4 weeks after TACE, and then avelumab 14 days (or 14-18 days) upon completion of SBRT (see Study Scheme, 6.3 TACE, 6.4 SBRT, and 6.5 Checkpoint Inhibitor: Avelumab). The study protocol teaches that the TACE procedure comprises a femoral artery puncture wherein the aim is to deliver a sufficient amount of emulsion to tumor without retrograde flow; in the case bi-lobed HCC or super-selective cannulation is not possible, the emulsion will be injected to hepatic artery proper that distal to origin of gastro-duodenal artery which is followed by embolizat8in with gelfoam pellets (i.e., microspheres) of 1mm diameter mixed with 40mg of gentamicin (see 6.3.1 Procedure). The study protocol disclose that successful downstage and disease control (as defined by complete response, partial response and stable disease) will be evaluated for resection or transplantation of HCC (see Study Scheme; 7.2 Decision on Resectability, Subsequent Treatment and Treatment Failure).
As such, the START-FIT Study Protocol anticipates the present invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Chiang and Shiina
Claims 1-5, 9-10, and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Chiang et al (Journal of clinical oncology: official journal of the American Society of Clinical Oncology. , 2022, Vol.40, p.4091; published: 06/22/2022) as evidenced by Kotsifa et al (J. Pers. Med. 2022, 12, 436) and Lencioni et al (Semin Intervent Radiol 2013;30:3–11) as applied to claims 1-5, 9-10, and 14-18 above, and further in view of Shiina et al (Am J Gastroenterol 2012; 107:569–577).
Chiang et al disclose of a study investigating the safety and efficacy of sequential TACE and SBRT followed by avelumab in patients with locally advanced HCC (see Background). Patients with locally advanced HCC not suitable for curative resections were eligible wherein all patients had HCC ≥ 5cm, tumor nodules ≤3, and child-Pugh A5-B7 liver function (see Methods). Patients underwent single episode of TACE followed by 5-fraction SBRT (28 days afterwards), followed by avelumab (10 mg/kg) 14 days afterwards and every 2 weeks thereafter (see Methods). The sample size assumed that around 20% patients amendable to surgery after experimental treatment compared to 5% of historical institutional results after TACE (see Methods). 33 patients were enrolled and the median sum of diameter of lesion(s) was 15.1 cm, and 21 (63.6%) had macrovascular invasion (see Results). After a median follow-up of 17.2 months, 3 (9.1%) patients had tumor downstaged with curative surgery done (see Results). The objective response was 62.5%, of whom 15 had complete response (CR) (43.8%) and 6 had partial response (18.7%) (see Results). The median overall survival (OS) and progression-free survival was 30.3 months and 20.7 months, respectively (see Results). All three patients with surgery done were alive at 2 years; for 15 patients had CR, the 2-year OS rate was 92.9% without surgery (see Results).
While Chiang et al does not explicitly disclose of the TACE comprising infusing a chemotherapeutic agent and an embolic particle as recited in instant claims 14-17, it was known in the art that the form of TACE used in HCC comprises using an embolic microsphere (e.g., degradable starch microsphere, gelatin, or non-resorbable) loaded with a chemotherapeutic agent as evidenced by Kotsifa et al and Lencioni et al.
Chiang et al fails to teach of the claimed method further comprising treating the subject with radiofrequency ablation (RFA). This is remedied by Shiina et al.
Shiina et al disclose that RFA is widely performed for HCC (see Abstract). Specifically, Shiina et al disclose that RFA was the treatment of choice in HCC patients satisfying the following criteria: (i) ineligible for surgical resection/liver transplantation or patient refusal for surgery; (ii) no extrahepatic metastasis/vascular invasion; and (iii) no other malignancies that may determine the patient’s prognosis see pages 569-570). Shiina et al performed RFA on Child-Pugh class A or B patients, a single tumor ≤5 cm in diameter, or three or fewer tumors ≤3 cm in diameter; in cases beyond these conditions, Shiina et al performed RFA on patients who were likely to benefit from this procedure for possible cure or prolongation of life (see page 570, left col.). With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% and 27.3%, respectively (see Abstract). 5- and 10-year local tumor progression rates were both 3.2%; and the distant recurrence rates were 74.8% and 80.8%, respectively (see Abstract). Thus, Shiina et al demonstrate that RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure.
Therefore, it would have been obvious at the time of the present invention to combine the teachings Chiang et al and Shiina et al to develop the present invention because the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering TACE, SBRT, and avelumab that significantly improved the survival rates of unresectable, locally advanced HCC patients in combination with RFA as taught in the references above, one would achieve a method for treating unresectable, locally advanced HCC.
Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. As disclosed in the art, these methods (i.e., TACE, SBRT, RFA, and avelumab) are known to treat HCC; thus, it would be prima facie obvious that the combination of these methods would treat HCC.
START-FIT Study Protocol and Shiina
Claims 1-5, 9-10, and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over START-FIT v4 Study Protocol (uploaded online: 07/13/2022) as applied to claims 1-5, 9-10, and 14-18 above, and further in view of Shiina et al (Am J Gastroenterol 2012; 107:569–577).
The study protocol investigates the concept of combined TACE and SBRT followed by immune checkpoint inhibitor as a neo-adjuvant treatment in unresectable HCC patients (see entire document). Specifically, the study protocol assessed the safety and efficacy of the sequential administration of TACE and SBRT followed by avelumab in intermediate to advanced HCC patients (i.e., those diagnosed with unresectable HCC) (see Study Design and Inclusion Criteria). A total of 33 patients will be accrued to assess the potential benefit of combined TACE and SBRT followed by avelumab (see Study Participants). Protocol treatment must be within 28 days after study registration wherein TACE is first, followed by SBRT 4 weeks after TACE, and then avelumab 14 days (or 14-18 days) upon completion of SBRT (see Study Scheme, 6.3 TACE, 6.4 SBRT, and 6.5 Checkpoint Inhibitor: Avelumab). The study protocol teaches that the TACE procedure comprises a femoral artery puncture wherein the aim is to deliver a sufficient amount of emulsion to tumor without retrograde flow; in the case bi-lobed HCC or super-selective cannulation is not possible, the emulsion will be injected to hepatic artery proper that distal to origin of gastro-duodenal artery which is followed by embolizat8in with gelfoam pellets (i.e., microspheres) of 1mm diameter mixed with 40mg of gentamicin (see 6.3.1 Procedure). The study protocol disclose that successful downstage and disease control (as defined by complete response, partial response and stable disease) will be evaluated for resection or transplantation of HCC (see Study Scheme; 7.2 Decision on Resectability, Subsequent Treatment and Treatment Failure).
The study protocol fails to teach of the method further comprising treating the subject with RFA. This is remedied by Shiina et al.
Shiina et al disclose that RFA is widely performed for HCC (see Abstract). Specifically, Shiina et al disclose that RFA was the treatment of choice in HCC patients satisfying the following criteria: (i) ineligible for surgical resection/liver transplantation or patient refusal for surgery; (ii) no extrahepatic metastasis/vascular invasion; and (iii) no other malignancies that may determine the patient’s prognosis see pages 569-570). Shiina et al performed RFA on Child-Pugh class A or B patients, a single tumor ≤5 cm in diameter, or three or fewer tumors ≤3 cm in diameter; in cases beyond these conditions, Shiina et al performed RFA on patients who were likely to benefit from this procedure for possible cure or prolongation of life (see page 570, left col.). With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% and 27.3%, respectively (see Abstract). 5- and 10-year local tumor progression rates were both 3.2%; and the distant recurrence rates were 74.8% and 80.8%, respectively (see Abstract). Thus, Shiina et al demonstrate that RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure.
Therefore, it would have been obvious at the time of the present invention to combine the teachings of the START-FIT Study Protocol and Shiina et al to develop the present invention because the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering TACE, SBRT, and avelumab that significantly improved the survival rates of unresectable, locally advanced HCC patients in combination with RFA as taught in the references above, one would achieve a method for treating unresectable, locally advanced HCC.
Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. As disclosed in the art, these methods (i.e., TACE, SBRT, RFA, and avelumab) are known to treat HCC; thus, it would be prima facie obvious that the combination of these methods would treat HCC.
Su, Tanaka, and Shiina
Claims 1-4, 9-10, 14-17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Su et al (BMC Cancer (2016) 16:834), and further in view of Jiang et al (Cancers 2023, 15, 50; published online: 12/22/2022) and Shiina et al (Am J Gastroenterol 2012; 107:569–577).
Su et al disclose of the long-term survival analysis in combined TACE and SBRT versus SBRT monotherapy for unresectable HCC >5cm (see Title). Su et al disclose that TACE is frequently used as a local treatment option for unresectable or non-transplantable HCC, which imparts a survival benefit compared to best supportive care (see page 5, right col.). 77 patients received SBRT followed by transarterial embolization (TAE) or TACE, wherein the dose of SBRT was 30-50 Gy which was prescribed in 3-5 fractions (see Abstract). Su et al disclose that the TACE procedure comprises selective arteriography of the hepatic artery to locate the tumor and after identifying the tumor-feeding artery, a mixture of 5-20 mL Lipiodol and 30-40 mg/m2 cisplatinum or fluorouracil glycosides 750-1000 mg was slowly injected through the catheter, which was followed by gelatin sponge particle Gelfoam embolization (see page 2, right col.). The median follow-up period was 20.5 months; the median OS in the TAE/TACE+SBRT group was 42.0 months versus 21.0 months in the SBRT group (see Abstract). The 1-, 3- and 5-year OS was 75.5, 50.8, and 46.9% in the TAE/TACE+SBRT group and was 62.4, 32.9, and 32.9% in the SBRT group, respectively (see Abstract). Lastly, the 1-, 3- and 5-year distant metastasis-free survival (DMFS) was 66.3, 44.3, and 40.6% in the TAE/TACE+SBRT group and was 56.8, 26.1, and 17.4% in the SBRT group, respectively (see Abstract).
Su et al fail to disclose of a method of treating HCC comprising administering an immune checkpoint inhibitor and RFA. This is remedied by Jiang et al and Shiina et al, respectively.
Jiang et al teach of SBRT plus immune checkpoint inhibitors (ICIs) in HCC and cholangiocarcinoma (CCA) (see Title). Jiang et al teach that until mid-2020, sorafenib (a TKI) was offered as a first-line treatment, but now atezolizumab/bevacizumab can be offered if there are no contraindications for ICI and VEGF inhibitors (see page 2). Jiang et al disclose that pre-clinical evidence suggests that immunotherapy works synergistically with radiation to enhance tumor-specific immune responses (see page 2; Figure 1). Solid tumors can avoid anti-tumor immunity by downregulating antigen presentation and CD8+ cytotoxic T-cell activity; immunotherapy counteracts this by either stimulating activating regulators of T-cell function (OX40) or inhibiting negative regulators such as ICI, including PD-1, PD-L1, and CTLA-4 because anti-PD-L1 inhibits tumor immune evasion (see pages 2-3). With respect to HCC, Jiang et al disclose of several trials investigating SBRT and ICIs such as TACE + SBRT followed by durvalumab + tremlimumab, TACE + SBRT followed by avelumab every 2 weeks (see Table 2). Jiang et al disclose that anti-tumor responses can be enhanced by adding immunotherapy to radiation (concurrent vs. sequential), but the response is short-lived; continuing immunotherapy post-radiation could make that response durable (see page 4). In clinical practice, this was practically translated to SBRT plus ICI in NSCLC where durvalumab was continued after SBRT for locally advanced tumors (see page 4).
Lastly, Shiina et al disclose that RFA is widely performed for HCC (see Abstract). Specifically, Shiina et al disclose that RFA was the treatment of choice in HCC patients satisfying the following criteria: (i) ineligible for surgical resection/liver transplantation or patient refusal for surgery; (ii) no extrahepatic metastasis/vascular invasion; and (iii) no other malignancies that may determine the patient’s prognosis see pages 569-570). Shiina et al performed RFA on Child-Pugh class A or B patients, a single tumor ≤5 cm in diameter, or three or fewer tumors ≤3 cm in diameter; in cases beyond these conditions, Shiina et al performed RFA on patients who were likely to benefit from this procedure for possible cure or prolongation of life (see page 570, left col.). With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% and 27.3%, respectively (see Abstract). 5- and 10-year local tumor progression rates were both 3.2%; and the distant recurrence rates were 74.8% and 80.8%, respectively (see Abstract). Thus, Shiina et al demonstrate that RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure.
As such, it would have been obvious to combine the teachings of Su et al, Jiang et al, and Shiina et al to develop the claimed method because the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering TACE+SBRT that significantly improved the survival rates of unresectable, locally advanced HCC patients in combination with an ICI and RFA as taught in the references above, one would achieve a method for treating unresectable, locally advanced HCC.
Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. As disclosed in the art, these methods (i.e., TACE, SBRT, RFA, and ICIs) are known to treat HCC; thus, it would be prima facie obvious that the combination of these methods would treat HCC.
Jacob, Jiang, and Shiina
Claims 1-4, 9-10, 14-17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Jacob et al (HPB 2015, 17, 140–149), and further in view of Jiang et al (Cancers 2023, 15, 50; published online: 12/22/2022) and Shiina et al (Am J Gastroenterol 2012; 107:569–577).
Jacob et al teach of adjuvant SBRT following TACE in patients with non-resectable HCC tumors of ≥3 cm (see Title). TACE is the initial intervention most commonly performed, but it rarely eradicates intermediate-stage HCC in patients who are not candidates for surgical resection or tumor ablation (see Abstract; page 140, right col.). Patients taking chemotherapeutic agents before and/or after the procedure were included in the study (see page 141, right col.). Jacob et al disclose that the TACE procedures used lipiodol and drug-eluting beads (see page 144, right col.). However, Jacob et al disclose that local recurrence was significantly decreased in the TACE+SBRT group (10.8%) in comparison with the TACE-only group (25.8%) (see Abstract). After censoring for liver transplantation, overall survival was found to be significantly increased in the TACE+SBRT group compared with the TACE-only group (33 months and 20 months, respectively) (see Abstract).
Jacob et al fail to disclose of a method of treating HCC comprising administering an immune checkpoint inhibitor and RFA. This is remedied by Jiang et al and Shiina et al, respectively.
Jiang et al teach of SBRT plus immune checkpoint inhibitors (ICIs) in HCC and cholangiocarcinoma (CCA) (see Title). Jiang et al teach that until mid-2020, sorafenib (a TKI) was offered as a first-line treatment, but now atezolizumab/bevacizumab can be offered if there are no contraindications for ICI and VEGF inhibitors (see page 2). Jiang et al disclose that pre-clinical evidence suggests that immunotherapy works synergistically with radiation to enhance tumor-specific immune responses (see page 2; Figure 1). Solid tumors can avoid anti-tumor immunity by downregulating antigen presentation and CD8+ cytotoxic T-cell activity; immunotherapy counteracts this by either stimulating activating regulators of T-cell function (OX40) or inhibiting negative regulators such as ICI, including PD-1, PD-L1, and CTLA-4 because anti-PD-L1 inhibits tumor immune evasion (see pages 2-3). With respect to HCC, Jiang et al disclose of several trials investigating SBRT and ICIs such as TACE + SBRT followed by durvalumab + tremlimumab, TACE + SBRT followed by avelumab every 2 weeks (see Table 2). Jiang et al disclose that anti-tumor responses can be enhanced by adding immunotherapy to radiation (concurrent vs. sequential), but the response is short-lived; continuing immunotherapy post-radiation could make that response durable (see page 4). In clinical practice, this was practically translated to SBRT plus ICI in NSCLC where durvalumab was continued after SBRT for locally advanced tumors (see page 4).
Lastly, Shiina et al disclose that RFA is widely performed for HCC (see Abstract). Specifically, Shiina et al disclose that RFA was the treatment of choice in HCC patients satisfying the following criteria: (i) ineligible for surgical resection/liver transplantation or patient refusal for surgery; (ii) no extrahepatic metastasis/vascular invasion; and (iii) no other malignancies that may determine the patient’s prognosis see pages 569-570). Shiina et al performed RFA on Child-Pugh class A or B patients, a single tumor ≤5 cm in diameter, or three or fewer tumors ≤3 cm in diameter; in cases beyond these conditions, Shiina et al performed RFA on patients who were likely to benefit from this procedure for possible cure or prolongation of life (see page 570, left col.). With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% and 27.3%, respectively (see Abstract). 5- and 10-year local tumor progression rates were both 3.2%; and the distant recurrence rates were 74.8% and 80.8%, respectively (see Abstract). Thus, Shiina et al demonstrate that RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure.
As such, it would have been obvious to combine the teachings of Jacob et al, Jiang et al, and Shiina et al to develop the claimed method because the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering TACE+SBRT that significantly improved the survival rates of unresectable, locally advanced HCC patients in combination with an ICI and RFA as taught in the references above, one would achieve a method for treating unresectable, locally advanced HCC.
Further, because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. As disclosed in the art, these methods (i.e., TACE, SBRT, RFA, and ICIs) are known to treat HCC; thus, it would be prima facie obvious that the combination of these methods would treat HCC.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Zheng et al (Front. Oncol. (2021) 11:713432) teach that patients with recurrent HCC in the TACE+RFA treatment group and the repeat hepatectomy group had similar OS and PFS regardless of the patient’s tumor diameter, but the TACE-RFA group was safer and more minimally invasive (see Abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
Prosecution Insights