DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
2. Claims 1-10 are pending.
Information Disclosure Statement
2. No information disclosure statement was present at the time of this office action.
Claim Objections
3. In claim 1, 7, 8, 9, and 10, the “TRAIL” acronym is not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purpose of examining, the “TRAIL” is interpreted to mean “TNF-related apoptosis-inducing ligand”. An acronym should only be defined the first time it appears in the claims. Appropriate correction is required.
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.
4. Claims 1-7, and 9 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.
The instant claims are drawn to a method of reducing toxic side effects in a subject undergoing cancer treatment, comprising administering an effect amount of a trail compound to the subject and TRAIL compound can be a TRAIL inducing compound, TRAIL protein, or A TRAIL variant.
The specification teaches administering an effective amount of a TNF-related apoptosis inducing ligand (TRAIL) compound to a subject who is undergoing cancer therapy. The specification teaches the TRAIL compounds include TRAIL and conservative derivatives or variants of TRAIL, as well as TRAIL inducing compounds including ONC201 and TLY012. Although the claims are inclusive of a specifically disclosed ONC201 and TLY012, the claims are not limited to the specific compounds and instead are inclusive analogs and derivatives of the recited compounds. For example, the claims recite “ a TRAIL compound” , “TRAIL protein”, “ a TRAIL variant”, “a TRAIL inducing compound”. This is interpreted as encompassing any compound with a structure similar to TNF-related apoptosis inducing ligand. The specification recites “Functional-conservative derivatives may result from modifications and changes that may be made in the structure of a polypeptide and still obtain a functional molecule with desirable characteristics”, “Functional- conservative derivatives may also consist of a fragment of a polypeptide that retains its functionality”, “A functional-conservative derivative also includes a polypeptide which has at least 60% amino acid identity as determined by BLAST or FASTA algorithms, preferably at least 75%, more preferably at least 85%, still preferably at least 90%, and even more preferably at least 95%, and which has the same or substantially similar properties or functions as the native or parent protein to which it is compared. Two amino acid sequences are "substantially homologous" or "substantially similar" when greater than 80%, preferably greater than 85%, preferably greater than 90% of the amino acids are identical, or greater than about 90%, preferably greater than 95%, are similar”, and “A TRAIL inducing compound is a compound that increases the expression and/or activity of TRAIL in the subject”. This indicates, hundred, if not thousands, of possible molecules encompassed by the claims. The claim require that the TRAIL compound exhibit specific functions, but the specification provides no guidance regarding which protein, small molecules, nucleic acids, or other molecules are capable of the required function. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of agents because, inter alia, the specification does not disclose a correlation between the necessary structure of the agonists and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function.
Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed agent may generically describe the agent’s function, it does not describe the agent itself. A definition by function does not suffice to define the genus because it is only an indication of what the agent does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of agents is highly variable (i.e., each TRAIL compound would necessarily have a unique structure; see MPEP
2434), the generic description of the substance is insufficient to describe the genus.
Thus, the encompassed TRAIL compounds have no correlation between their structure and function.
For example, the specification teaches Dulanermin as an example of a TRAIL variant. Ouyang, et al. teach Dulanermin, which is TRAIL variant, that was studied to determine the efficacy and safety for treatment for patients who have advanced non-smell-cell lung cancer. However, during the study, multiple patients had serious adverse effects including nausea, vomiting, liver function injury, renal function injury, death, cerebral infarction, epilepsy, respiratory failure, venous thrombosis, and pulmonary embolism. The study shows that the trail variant did not reduce toxic side effects but in fact induced them.
Zhong, et al. teach TRAIL compounds involving proteins and peptides such as a biomimetic vector developed for delivering pTRAIL to tumor; it contained an adenovirus μ peptide for pDNA condensation, a synthetic cyclic peptide for tumor-targeting and intracellular delivery, a pH-responsive synthetic fusogenic peptide for endosome escape, and a nuclear localization signal from human immuno-deficiency virus for intranuclear delivery. Lee et al. teach novel application of nanoparticles for the dual purpose of delivering and activating a heat-inducible gene vector that encodes TRAIL in adipose-derived mesenchymal stem cells that significantly arrest tumor growth. Gao et al. transfected pTRAIL into MSCs with a nonviral vector, prepared by linking low-molecular-weight polyethyleneimine (PEI) and β-cyclodextrin (β-CD)
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the fully described TRAIL compounds, and the claimed function(s), this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed TRAIL compounds and encompass a vast genus of compounds of varying biological genera. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Given the vast number of agents that are encompassed by the claims, the disclosure of a few species is not sufficiently representative of the broad genus of compounds encompassed by the claims. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed 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 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 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.
A variety of compounds are known in the art and may be identified by their effects. Examples include proteins, small molecules, or nucleic acids. The instant claims thereby encompass many genera of chemical and biological molecules, without any described structure that is required for the molecules to perform required functions.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). 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 Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). 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).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai 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.
The 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 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and 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. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
5. Claim(s) 1, 4, 5, 6, 7 and 8 is/are rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Stein, et al. (First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. Clin Cancer Res 1 August 2017; 23 (15): 4163–4169)
Claims 1, and 4-8 are drawn to a method of reducing toxic side effects in a subject undergoing cancer treatment comprising administering an effective amount of a TRAIL compound to the subject. Stein, et al. teach a method of administering an effective amount of ON201 in patients that underwent cancer treatment including radiotherapy, as recited in instant claim 1. Stein et al teach that administering a trail compound to patients that have undergone cancer treatment may offer clinical benefit without imposing the typical toxicities of anticancer therapies, as recited in instant claim 1. Stein, et al. further teaches that patient(s) underwent cancer treatment including radiotherapy (Patient population paragraph), as recited in instant claim 4. Stein, et al. also teach that some subjects in the patient population, which are human (Patient population paragraph), had lung cancer (Patient outcomes, paragraph 2 and Figure 3A.), as recited in instant claims 5 and 6. Stein, et al. further teaches ONC201-induced activation (Introduction, paragraph 1), which is a TRAIL inducing compound, as recited in instant claims 7 and 8.
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.
6. Claim(s) 1, 2, 3, 4, 5, 6, 7 and 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stein, et al. (First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. Clin Cancer Res 1 August 2017; 23 (15): 4163–4169) in view of Grosse-Wilde, et al. (TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. JCI 13 December 2007; 10.1172/JCI29900).
Stein, et al. teach a method of administering an effective amount of ON201 in patients that underwent cancer treatment including radiotherapy, as recited in instant claim 1. Stein et al teach that administering a trail compound to patients that have undergone cancer treatment may offer clinical benefit without imposing the typical toxicities of anticancer therapies, as recited in instant claim 1. Stein, et al. further teaches that patient(s) underwent cancer treatment including radiotherapy (Patient population paragraph), as recited in instant claim 4. Stein, et al. also teach that some subjects in the patient population, which are human (Patient population paragraph), had lung cancer (Patient outcomes, paragraph 2 and Figure 3A.), as recited in instant claims 5 and 6. Stein, et al. further teaches ONC201-induced activation (Introduction, paragraph 1), which is a TRAIL inducing compound, as recited in instant claims 7 and 8.
However, Stein, et al. does not teach specifically teach the toxic side effect of inflammation which is radiation induced pulmonary pneumonitis.
Grosse-Wilde, et al. demonstrate a correlation between TRAIL-R -/- mice had decreased survival rate following irradiation and unique tissue phenotyping including chronic inflammation and are sensitized to sporadic radiation-induced pneumonitis. Therefore, one of ordinary skill would reasonably conclude that when TRAIL is present survival rates are increased and sensitivity to radiation-induced pneumonitis decrease. Grosse-Wilde, et al. further teach that TRAIL-R deficient mice provides a new model system to study the late toxic effects of ionizing radiation. A person having ordinary skill in the art could reasonably interpret the findings of Grosse-Wilde, et al., to be incorporated in the study by Stein, et al., to study efficacy of TRAIL-R, and TRAIL compound on patients with toxic side effects such as an inflammation, specific to radiation induced pneumonitis caused by cancer treatment.
The Supreme Court decided that a claim can be proved obvious merely by showing that the combination of known elements was obvious to try. In this regard, the Supreme Court explained that, “[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has a good reason to pursue the known options within his or her technical grasp.” An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of the case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. Therefore, choosing from a finite number of identified, predictable solutions, with a reasonable expectation for success, is likely to be obvious to a person if ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, E.).
7. Claims 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Stein, et al. and Grosse-Wilde, et al. as applied to claims 1-8 above, in further view of Jhaveri, et al. (Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo. Cancer Biology & Therapy, 22(10–12), 607–618).
The teachings of Stein et al. and Grosse-Wilde et al have been described previously.
Stein et al. and Grosse-Wilde et al do not teach a TRAIL protein specially TLY012.
However, Jhaveri et al. teaches analyzing the preclinical potential of TLY012 in combination with ONC201 in vivo, to show the combination of ONC201 and TLY012 can induce selective, synergistic apoptosis in vitro and significantly delays tumor xenograft growth in vivo. This combination treatment shows marked efficacy in models that are both sensitive and resistant to ONC201-induced apoptosis providing a promising outlook for patients whose tumors do not respond to ONC201 and providing potential for regression in patients’ tumors that do respond to ONC201.
It would have been obvious to someone of ordinary skill in the art before the effective
filling date of the claimed invention to have modified Stein, et al. and Grosse-Wilde, et al. to incorporate the teachings of Jhaveri et al, by implementing TLY012 as a TRAIL protein as Jhaveri, et al. used both compounds in a synergistic manner.
8. Claims 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Stein, et al. and Grosse-Wilde, et al. as applied to claims 1-8 above, and further in view of Sokoloff, et al. (US Patent No. 11,767,353; Filed 04/06/2021).
The teachings of Stein et al. and Grosse-Wilde et al have been described previously.
Stein et al. and Grosse-Wilde et al do not teach a TRAIL protein specially TLY012.
However, Sokoloff, et al. teaches that two weeks after the tumor transplantation, mice were injected with TLY012 via intravenous (IV) injection (10 mg/kg, every other day) for 2 weeks, while control mice received PBS (paragraph 328) as recited in instant claim 10. The antitumor/fibrogenic efficacy of TLY012 was investigated in PSC/AsPC-1 (human primary pancreatic stellate cells/pancreatic adenocarcinoma cell line) tumor-bearing mice (paragraph 329). The data showed that only TLY012 induced apoptosis among tested cytotoxic agents including Gemcitabine, Doxorubicin, Cisplatin, 5-FU, and Irinotecan (Figure. 11).
It would have been obvious to someone of ordinary skill in the art before the effective
filling date of the claimed invention to have modified the method of Stein, et al. to include the toxic side effects of Grosse-Wilde, et al and specifically administer the TLY012 of Sokoloff, et al. teach thatTLY012 induced apoptosis.
Conclusion
9. No claims are allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674