DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
This application is a continuation of U.S. Patent Application No. 17/977,385, filed October 31, 2022, which is a continuation application of U.S. Patent Application 17/703,643, filed March 24, 2022, which is a continuation application of U.S. Patent Application 17/379,565, filed July 19, 2021, which is a continuation of U.S. Patent Application 16/950,490, filed November 17, 2020, which is a continuation application of U.S. Patent Application No. 16/804,291, filed February 28, 2020, which is a continuation application of U.S. Patent Application No. 16/454,791, filed June 27, 2019, which is a continuation application of U.S. Patent Application No. 15/546,179, filed July 25, 2017, which is a national stage entry under 35 U.S.C. § 371(b) of PCT International Application No. PCT/US2016/014121, filed January 20, 2016, which claims the benefit of U.S. Provisional Application No. 62/247,956 filed October 29, 2015, and U.S. Provisional Application No. 62/107,866 filed January 26, 2015
The examiner finds support for the claimed subject matter in the earlier filed U.S. Provisional Application No. 62/107,866 filed January 26, 2015. Therefore, January 26, 2015 is being considered as the effective filing date for the claimed subject matter in this action. Note, the examiner finds earliest description for the ER stress mechanism and suggested ER stress inhibitors in the U.S. Provisional Application No. 62/247,956 filed October 29, 2015.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 28 December of 2023 is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Specification
The instant specification is objected to because it does not comply with 37 C.F.R. § 1.821(d) which requires a reference to a particular sequence identifier (SEQ ID NO:) be made in the specification and claims wherever a reference is made to that sequence. Specifically, Table 5 on page 40 therein presents a plurality of nucleotide sequences without employing the required sequence identifiers. Correction is required. See M.P.E.P. 2422.
The instant specification is objected to because the table presented on page 40 of the instant specification does not comply with 37 C.F.R. 1.58 (c), which states that:
Chemical and mathematical formulae and tables must be presented in compliance with § 1.52(a) and (b), except that chemical and mathematical formulae or tables may be placed in a landscape orientation if they cannot be presented satisfactorily in a portrait orientation. Typewritten characters used in such formulae and tables must be chosen from a block (nonscript) type font or lettering style having capital letters which are at least 0.21 cm. (0.08 inch) high (e.g., elite type). A space at least 0.64 cm. (1/4 inch) high should be provided between complex formulae and tables and the text. Tables should have the lines and columns of data closely spaced to conserve space, consistent with a high degree of legibility.
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.
ENABLEMENT
Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention stated in Amgen Inc. v. Sanofi, 598 U.S. 594 (2023), the specification must enable the full scope of the claimed invention without undue experimentation. The specification is not enabling for the scope of Claim 1 without undue experimentation, specifically regarding a method of treating amyotrophic lateral sclerosis (ALS) in a human patient by the administration thereto of a compound of unspecified constitution which increases the expression of the major histocompatibility complex class I (MHC-1) molecule HLA-F by motor neurons in that patient.
An analysis of the enablement requirement under the factors set forth in re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988) established that undue experimentation is required to practice the scope of the claimed invention:
The Breadth of the Claims: The scope of claim 1 is exceptionally broad in two ways. First, it entails any patient (including humans). Second, it is not limited to the specific viral vectors built and tested in the specification, rather, it recites administering an open-ended functional genus covering any “compound” that increases expression of HLA-F in motor neurons in the patient. The specification describes that such a “compound” may be selected from broad categories including drugs, peptides, or nucleic acids, and further describes suitable drugs as ER stress inhibitors, interferons, LPS, Ganoderma lucidum polysaccharides, topotecan, trichostatin A, PLGA nanoparticles, and mesoporous silicon microparticles, all of which are structurally and mechanistically disparate modalities (see page 16 of specification).
The Nature of the Invention: The invention is related to highly complex neuro-immune and molecular biology pathways. Specifically, it aims to modulate the major histocompatibility complex class I (MHC-1) molecule, HLA-F, in motor neurons, to treat a fatal, complex neurodegenerative disease, ALS.
The State of the Prior Art: The prior art establishes that translating preclinical therapies to human clinical efficacy in ALS is notoriously difficult and highly prone to failure. As documented in the last paragraph on page 1142 of the DiBernardo et al. publication (Biochimica et Biophysica Acta 1762:1139–1149, 2006):
“Several experimentally induced mutations – G93A, G37R and G85R – have been developed in transgenic mouse models, however, the SOD1G93A mutant is primarily used for therapeutic research. The SOD1G93A mutant generally recapitulates human disease, including cardinal findings of motor neuron loss, microgliosis and astrocytosis [6,118] and is a powerful tool for dissecting the biology of motor neuron disease. The major weakness of animal models for ALS thus far has been the de facto failure of these models to predict response in humans. Riluzole, first demonstrated to be effective in humans was later shown to be effective in the SOD1G93A mouse model. As experience has shown, the converse does not always hold and a number of compounds found to be effective in this model failed in humans, including vitamin E [113], gabapentin [114], topiramate [115], celecoxib [116], and creatine [117]. The reasons for discordant results between mouse and human trials are not fully understood but may relate to inherent differences between the mouse and human disease.”
This position is further supported by the Benatar publication (Neurobiology of Disease 26:1–13, 2007), the abstract of which states that the “therapeutic success in the superoxide dismutase (SOD1) mouse model of amyotrophic lateral sclerosis (ALS) has not translated into effective therapy for human ALS, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans.” The “Introduction” section on page 1 of Benatar further explains that:
“Since the identification of mutations in the SOD1 gene as an important cause of familial ALS (Rosen et al., 1993) and the generation of the SOD1 mouse model of ALS several years later (Gurney et al., 1994), there have been dozens of studies of a panoply of therapeutic agents in SOD1 mice. The choice of therapeutic agents in many clinical trials of human ALS (Cudkowicz et al., 2006; Groeneveld et al., 2003; Shefner et al., 2004) has been predicated, at least in part, on the efficacy of these drugs when studied in the SOD1 mouse (Drachman et al., 2002; Klivenyi et al., 1999). Nevertheless, success in human clinical trials has been extremely limited, calling into question the utility of such preclinical data for identifying therapeutic agents that are worthy of further study in humans”.
Thus, efficacy in this mouse model does not correlate to efficacy in humans.
Furthermore, Beghi E. et al., (Italian Amyotrophic Lateral Sclerosis Study Group. Neurology. 25;54(2):469-74.) evaluated “the efficacy of recombinant interferon beta (IFNbeta)-1a in the treatment of ALS;” however, the trial concluded “that IFNbeta-1a is not effective in the treatment of ALS,” see objective and conclusions. Beghi further teaches these findings “are in agreement with the negative results reported previously with IFN alfa and beta,” see discussion third paragraph.
The Level of One of Ordinary Skill in the Art: While the level of skill in neurobiology and molecular therapeutics is high, a high level of routine skill cannot overcome a total lack of structural guidance and clinical predictability.
The level of Predictability in the Art: The art establishes that treating ALS in humans is predictably unsuccessful. Because not one beneficial therapeutic protocol for the treatment of ALS in a human subject has ever been identified by employing in vitro experiments relating the causes of motor neuron death, or any other activity, or by employing in vivo results from the treatment of SOD1G93A mice, in spite of the remarkably high skill level of the routine neurobiologist, one of skill can reasonably predict that any proposed method of treating ALS in a human subject will be inoperable in the absence of evidence to the contrary. Whereas the instantly claimed method is based upon sound scientific reasoning, one of skill would find such reasoning inadequate because one would reasonably accept that each and every one of those failed therapeutic protocols discussed in the above references were also based upon equally sound scientific reasoning and experimental data.
As stated in the decision in Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir. 2005):
“Rasmusson argues that the enablement requirement of section 112 does not mandate a showing of utility or, if it does, it mandates only a showing that it is "not implausible" that the invention will work for its intended purpose. As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to ‘inventions’ consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the ‘inventor’ would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis. Because we have upheld the Board's determination of priority due to lack of enablement, it is unnecessary for us to address the Board's ruling regarding lack of adequate written description.”
The Amount of Direction of Guidance Presented by the Inventor: The specification provides guidance for viral-mediated gene delivery, specifically an AAV9 vector encoding an HLA-F overexpression construct. The specification provides no structural guidance, selection rules, or common chemical features that would allow a skilled artisan to identify or design other classes of compounds such as small molecules, peptides, or biologics that would increase HLA-F expression in motor neurons. Although various candidate compounds are listed on Pg. 16 the specification provides no meaningful instruction regarding which of those compounds actually perform the claimed function or how to identify additional compounds within the claimed functional genus.
The Presence or Absence of Working Examples: The specification does not describe a working example of the successful administration of the claimed method to a human subject for beneficial effect. Example 22 of the instant application describes the results of the administration of the claimed method to the treatment of a mammal afflicted with ALS, which involved the administration of an AAV9 viral vector encoding “H2-Kb” or “H2-Db” to SOD1G93A mice. Because there is no correlation between the efficacy of a therapeutic protocol in the treatment of ALS in SOD1G93A mice and the treatment of ALS in humans, the specification does not provide the skilled artisan with a reasonable expectation that the administration of the claimed method to the treatment of ALS in a human subject will be beneficial thereto. Furthermore, the specification provides zero working examples of non-nucleic acid chemical compounds (such as small molecules or synthetic peptides) that successfully upregulate endogenous HLA-F in motor neurons within any animal model or patient. While page 16 lists prospective chemical agents (e.g., topotecan, LPS, etc.), no data or experimental protocols are provided to show that these distinct structural classes actually modulate this specific pathway.
The Quantity of Experimentation Necessary: To practice the full scope of claim 1 (i.e., a method to treat any ALS patient with any compound that increases HLA- expression), a person skilled in the art would be required to engage in an open-ended, rigorous and creative research project. This would require screening vast chemical libraries to find small molecules or peptides that can cross the blood-brain barrier, target motor neurons, safely upregulate HLA-F, and then successfully translate that mechanism into human patients despite a complete absence of predictive animal models or clinical data.
Accordingly, because the quantity of experimentation required is undue, the specification fails to comply with the enablement requirement of 25 U.S.C 112(a).
WRITTEN DESCRIPTION
Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim Scope
Claim 1 is directed to a broad method of treating amyotrophic sclerosis (ALS) in a patient, including a human patient, by administering “a compound” that increases the expression of the major histocompatibility complex class I (MHC-1) molecule HLA-F within motor neurons of the patient.
The “compound,” as recited in claim, is defined by its function (i.e., the ability to increase HLA-F expression in motor neurons) and is therefore being interpreted by the examiner as a functional genus encompassing a broad and structurally diverse set of possible agents, including but not limited to small molecules, peptides, biologics, nucleic acids, viral vectors, and particulate delivery systems.
However, the specification does not describe possession of that broad genus. While the specification teaches that the compounds can be selected from the group consisting of drugs, peptides, and nucleic acids, and further teaches suitable drugs may be selected from interferons, LPS, Ganoderma lucidum polysaccharides, topotecan, trichostatin A, polylactic-co-glycolic acid nanoparticles, or mesoporous silicon microparticles, the disclosure provides working experimental support for a viral vector-based nucleic acid construct embodiment, specifically an AAV9 vector delivering an MHC-1/HLA-F transgene in cultured cells and in a SOD1G93A mouse model (see pages 16 and 29-37 of specification). Thus, the scope of the specification is insufficient to support the scope of the claim.
Failure to Disclose a Representative Number of Species to Support the Broad Genus
To satisfy the written description requirement for a broad functional genus, the specification must either:
disclose a representative number of species that reflect the structural variation within that genus, or
identify common structural features shared by its members sufficient to permit a person of ordinary skill in the art to recognize the members of that genus.
See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014); Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997)).
The instant specification does neither.
Failure to Disclose a Representative Number of Species Possessing the Claimed Function
While the specification identifies several named compounds for drugs and ER stress inhibitors, and broad categories of therapeutic agents, those compounds are disclosed only as prospective candidates. The specification does not provide experimental evidence demonstrating that the listed compounds on page 16 actually possess the claimed functional property of increasing HLA-F expression in motor neurons. Instead, experimental support is provided for one species: an AAV9-mediated nucleic acid construct encoding HLA-F. Accordingly, although multiple candidate compounds are listed, the specification fails to disclose a representative number of species shown to perform the claimed function, and therefore does not support the full breadth of the claimed functional genus.
Failure to Identify Common Structural Features Defining the Claimed Genus
The compounds identified in the specification are structurally and mechanistically unrelated, including: ER stress inhibitors such as lithium, drugs such as the small-molecule topoisomerase inhibitor topotecan, peptides such as the bacterial endotoxin outer membrane component (LPS), fungal polysaccharide such as Ganoderma lucidum, synthetic polymer nanoparticles such as PLGA, and nucleic acids such as a viral expression vector driven by a CMV promotor. The specification does not identify any common structural characteristics, molecular scaffolds, shared chemical motif, or other unifying structural feature linking these highly disparate agents to the claimed function of increasing HLA-F expression in motor neurons. Absent such structural guidance, the specification does not define a recognizable or bounded genus, but instead provided only a list of unrelated possibilities.
Functional Language or Mechanistic Hypotheses Do Not Establish Possession
The specification proposes a mechanism of modulating HLA-F expression by inhibition of ER stress; however, there is a lack of description for the structure-function correlation for ER stress inhibitors and the recited mechanism. The examiner notes that example 20 outlines a specific mechanistic hypothesis regarding ER stress. The specification states that astrocytes in the ALS environment produce ER stress by acting as sarco-endoplasmic reticulum calcium ATPase (SERCA) inhibitors (modeled via thapsigargin), which consequently leads to a loss of MHC-1 expression in over 76% of motor neurons. Based on this negative correlation (that inducing ER stress decreases MHC-1 expression), the applicant hypothesizes that administering an ER stress inhibitor will serve as a compound that increases or maintains HLA-F expression. However, the disclosure does not provide any data, assays, or experimental proof demonstrating that the administration of an ER stress inhibitor successfully reverses this pathway to increase or restore functional HLA-F expression in motor neurons. Proving that a stressor downregulated a target molecules does not constitute a written description or a reduction to practice of a method showing that a broad class of generic inhibitors safely and effectively upregulated that target in a therapeutic environment.
In summary, the disclosure does not provide any data establishing that any of the chemical species listed on page 16 (e.g., lithium, interferons, topotecan, trichostatin A, etc) actually increase the expression of HLA-F in motor neurons. Merely listing potential drugs and therapeutic pathways, uncoupled from any demonstrated functional capability to achieve the claimed therapeutic result, constitutes nothing more than an unproven hypothesis or a list of “respectable guesses” (Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir. 2005)). It does not convey to the skilled artisan that the inventor has actual possession of a method utilizing these non-viral structural variants at the time of filing. Therefore, the specification fails to provide evidence of a reduction to practice of a representative number of species of the required compound, even in the treatment of SOD1G93A mice.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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, Ram Shukla can be reached at (571) 272-0735. 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.
/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights