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 .
The preliminary amendment filed 12/20/24 is acknowledged. Claims 1 and 6-14 have been amended. Claims 16-31 have been added. Claims 1-14 and 16-31 are pending and under examination.
Information Disclosure Statement
The information disclosure statements filed on 5/3/23, 1/28/25, 7/15/25, and 9/16/25 have been considered. A signed copy is enclosed.
It should be noted that the disclosure statement filed 5/3/23 list a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See page 59.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The use of the term Lipofectamine™ and FastPrep-24™, 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
Claim 1 is objected to because of the following informalities: the term “IFN-λ” contains an acronym and/or abbreviation that should be spelled out upon first occurrence. 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.
Claims 1-14 and 16-31 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 treating or preventing a viral-induced disorder comprising administering to a subject an effective amount of a pharmaceutical composition comprising an mRNA encoding an IFN-λ, thereby treating or preventing the viral-induced disorder. The dependent claims state that the viral-induced disorder is a viral-induced respiratory disorder and names rhinovirus, influenza virus, parainfluenza virus, metapneumovirus, respiratory syncytial virus, adenovirus, and coronavirus as viruses that cause the viral-induced respiratory disorder. The claims also state that the virus is a member of the Pneumoviridae, Orthomyxoviridae, Adenoviridae, Arenaviridae, Paramyxoviridae, Flaviviridae, Retroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Parvoviridae, Reoviridae, Herpesviridae or Hepadnaviridae family. The claims state that the virus is ARS-CoV, SARS-CoV-2, HCoV-NL63, or influenza.
Claims 18 is drawn to a method of treating or preventing a virus-induced exacerbation of a lung disease, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an mRNA encoding an IFNλ, thereby treating the virus induced exacerbation of the lung disease in the subject. The dependent claims state that the lung disease is asthma or chronic obstructive pulmonary disease.
Claim 20 is drawn to an mRNA comprising a coding region encoding an IFNλ1, polypeptide, an IFNλ2 polypeptide, an IFNλ3 polypeptide or a combination thereof.
The specification teaches that the IFNλ protein encoded by the mRNA comprised in the pharmaceutical composition can be any possible IFNλ protein, in particular IFNλ1 (also known as IL-29), IFNλ2(also known as IL-28A), or IFNλ3 (IL-28B) or any combination thereof. The specification teaches that the polyribonucleotide can further comprise unmodified or modified nucleotides, and mixture thereof. The specification teaches that the term modified nucleotide refers to any naturally or unnaturally occurring isomers of A, C, G, and U nucleotides as well as to any naturally occurring or non-naturally occurring analogs, alternative or modified nucleotide or isomer thereof having for example chemical modification or substituted residues. The specification teaches that modified nucleotides can have a base modification and/or a sugar modification, a phosphate group modification, or nucleotides that are synthesized post-transcriptionally by covalent modification of the nucleotides. The specification teaches that the modified nucleotide also encompasses nucleotides containing isotopes.
The specification teaches that prophylactic treatment with IFNλ1 mRNA reduced SARS-CoV2 and IAV virus load while Stop mRNA did not (See page 43). The specification teaches that does dependent reduction of virus load by recombinant IFNλ1 was observed, but was lower with recombinant protein compared to mRNA treatment (See page 43).
The specification discloses mRNA encoding IFNλ1 as set forth in SEQ ID NOs: 13-15 as encompassed mRNA species. However, the claims are not limited to these species and do not recite any structure of the mRNA. Instead, the claims encompass millions of mRNAs, comprising both modified and unmodified nucleotides or mixtures thereof, that encode any possible IFNλ protein. These mRNAs must be able to treat and prevent all of the thousands of viral-induced respiratory disorders. These mRNAs must also be able to treat or prevent any virus-induced exacerbation of a lung disease. The encompassed mRNAs have no correlation between their structure and these functions. The specification provides no guidance regarding which of the encompassed modified or unmodified mRNAs encoding any possible IFNλ are capable of each of the claimed functions, and a few example species does not sufficiently represent the vast breadth of the encompassed genus of mRNAs. 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.)
With the exception of treating SARS-CoV2 and IAV with mRNAs comprising the sequences set forth in SEQ ID NOs: 13-15, the skilled artisan cannot envision the detailed chemical structure of the encompassed mRNAs, 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.
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.
The use of mRNA for therapy is an unpredictable area of biotechnology. Baptista et al. (Pharmaceutics 2021, 13, 2090) teach that although mRNA holds great promise in therapy for numerous diseases, the main obstacle is the ability to specifically deliver it to target cells (See page 6). Baptista et al. teach one of the limitations of the use of mRNA as a therapeutic is its susceptibility to enzymatic degradation, particularly by ubiquitous RNAses in the blood and tissues (See page 6). Baptista et al. teach that in addition to RNAses, other barriers, such as the cell membrane, have to be surpassed (See page 6). Baptista et al. teach that naked mRNA does not have the necessary characteristics for its entry through the phospholipid bilayer, as this molecule has a negative charge and a large size and is hardly transported into the cell without its incorporation into a delivery system (See page 6). Baptista et al. teach that moreover, in in vivo application, intravenously administered naked mRNA is rapidly degraded and may even cause an immune response (See page 6). Baptista et al. teach that mRNA encapsulation by appropriate delivery systems is an essential requirement for this molecule to overcome those barriers (See page 6). Baptista et al. teach that numerous approaches have been used for mRNA delivery. Baptista et al. teach that physical delivery has started to be tested to increase the efficiency of mRNA uptake in vivo, but an increased cell death and limited access to target cells/tissues have been pointed out as disadvantages (See page 6). Thus, the there are many factors that have hindered the clinical progression of mRNA therapy, and one of skill in the art would not be able to predictably determine which mRNA, if any, would have therapeutic efficacy in the treatment of any given viral-induced respiratory disease or virus-induced exacerbation of a lung disease.
The use of interferon-λ in the context of viral infection is discussed by Hermant et al. (J Innate Immun 2014;6:563–574). Hermant et al. teach that one of the first studies reporting IFNλ antiviral activity in vivo demonstrated that intravaginal treatment of female mice with IFNλ prior to infection with herpes simplex virus-2 prevented virus replication in the vaginal mucosa (See page 564). Hermant et al. teach that using IFNλ receptor deficient mice, it was shown that the contribution of IFNλ to the control of viral infection greatly varied according the virus (See page 564 and table 1). For instance, studies showed no protective effect of IFNλ against infection with encephalomyocarditis virus, lymphocytic choriomeningitis virus, or vesicular stomatitis virus (See page 564). Similarly, no antiviral activity of IFNλ could be detected in mice against hepatotropic viruses, such as Rift Vallet fever, Lassa fever virus, or mutant strain of Thogoto virus (See page 564). IFNλ was found to have a modest but detectable antiviral activity in vivo against influenza virus, human metapneumovirus and severe acute respiratory syndrome coronavirus (See page 564). Additional studies carried out with influenza virus showed variable extents of protection mediated by IFNλ (See page 564). Hermant et al. teach that the contribution of IFNλ was much clearer in respiratory syncytial virus and IFNλ was shown to play a major role in the protection against rotavirus (See page 564). Thus, the antiviral activity of IFNλ depends on the virus, and it cannot be predicted which viral-induced disorders and virus-induced exacerbations of a lung disease would be amenable to treatment with the claimed mRNA encoding an IFNλ. The art supports that one of skill in the art would need guidance regarding the specific mRNA encoding an IFNλ that can be used for treating or preventing a viral-induced disorder or viral-induced lung exacerbation.
The claimed mRNA encodes a IFNλ protein that has specific required functions. The claims are not limited to a specific IFNλ, and broadly encompass any possible IFNλ protein. However, protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
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 Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
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). Given not only the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of representative number species across the breadth of the genus, one of skill in the art would not reasonably conclude that the full breadth of the claims meets the written description provision of 35 USC 112a).
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.
Claims 1-14 and 16-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating SARS-CoV2 and IAV comprising administering an mRNA comprising a sequence selected from SEQ ID NOs: 13-15 and a composition comprising an mRNA comprising a coding region encoding an IFNλ1, polypeptide, an IFNλ2 polypeptide, an IFNλ3 polypeptide or a combination thereof, wherein the coding region comprises SEQ ID NO: 1, 3, or 5, does not reasonably provide enablement for treating and preventing all viral-induced disorders by administering all mRNAs encoding any possible IFNλ and treating and preventing all virus-induced exacerbations of a lung disease by administering all mRNAs encoding any possible IFNλ, and all mRNA comprising a coding region of an IFNλ polypeptide. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention; 2) The breadth of the claims;
The nature of the invention is a method of treating or preventing a viral-induced disorder comprising administering to a subject an effective amount of a pharmaceutical composition comprising an mRNA encoding an IFN-λ, thereby treating or preventing the viral-induced disorder. The dependent claims state that the viral-induced disorder is a viral-induced respiratory disorder and names rhinovirus, influenza virus, parainfluenza virus, metapneumovirus, respiratory syncytial virus, adenovirus, and coronavirus as viruses that cause the viral-induced respiratory disorder. The claims also state that the virus is a member of the Pneumoviridae, Orthomyxoviridae, Adenoviridae, Arenaviridae, Paramyxoviridae, Flaviviridae, Retroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Parvoviridae, Reoviridae, Herpesviridae or Hepadnaviridae family. The claims state that the virus is SARS-CoV, SARS-CoV-2, HCoV-NL63, or influenza. Claim 18 is drawn to a method of treating or preventing a virus-induced exacerbation of a lung disease, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an mRNA encoding an IFNλ, thereby treating the virus induced exacerbation of the lung disease in the subject. The dependent claims state that the lung disease is asthma or chronic obstructive pulmonary disease. Claim 20 is drawn to an mRNA comprising a coding region encoding an IFNλ1, polypeptide, an IFNλ2 polypeptide, an IFNλ3 polypeptide or a combination thereof.
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the mRNA encoding an IFNλ for treating and preventing all viral-induced disorders and treating and preventing all virus-induced exacerbations of a lung disease, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
The claims are broad and inclusive of a vast genus of mRNAs that encode any possible IFNλ protein. The specification teaches that the IFNλ protein encoded by the mRNA comprised in the pharmaceutical composition can be any possible IFNλ protein, in particular IFNλ1 (also known as IL-29), IFNλ2(also known as IL-28A), or IFNλ3 (IL-28B) or any combination thereof. The specification teaches that the polyribonucleotide can further comprise unmodified or modified nucleotides, and mixture thereof. The specification teaches that the term modified nucleotide refers to any naturally or unnaturally occurring isomers of A,C,G, and U nucleotides as well as to any naturally occurring or non-naturally occurring analogs, alternative or modified nucleotide or isomer thereof having for example chemical modification or substituted residues. The specification teaches that modified nucleotides can have a base modification and/or a sugar modification, a phosphate group modification, or nucleotides that are synthesized post-transcriptionally by covalent modification of the nucleotides. The specification teaches that the modified nucleotide also encompasses nucleotides containing isotopes.
The claims are also broad and inclusive of all viral induced disorders and viral induced exacerbations of a lung disease. As noted above, the dependent claims state that the viral-induced disorder is a viral-induced respiratory disorder and names rhinovirus, influenza virus, parainfluenza virus, metapneumovirus, respiratory syncytial virus, adenovirus, and coronavirus as viruses that cause the viral-induced respiratory disorder. The claims also state that the virus is a member of the Pneumoviridae, Orthomyxoviridae, Adenoviridae, Arenaviridae, Paramyxoviridae, Flaviviridae, Retroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Parvoviridae, Reoviridae, Herpesviridae or Hepadnaviridae family. The claims state that the virus is ARS-CoV, SARS-CoV-2, HCoV-NL63, or influenza.
The specification also establishes the breadth of the claims by teaching that mRNA encoding an IFNλ polypeptide can be used for treating and/or preventing any possible viral-induced disorder. The specification teaches that viral-induced diseases which can be treated or prevented according to the present invention include diseases caused by a virus belonging to the family of Pneumoviridae, Orthomyxoviridae, Adenoviridae, Arenaviridae, Paramyxoviridae, Flaviviridae, Retroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Parvoviridae, Reoviridae, Herpesviridae or Hepadnaviridae. The specification teaches that viruses belonging to the family of Pneumoviridae include Human Metapneumo virus Viruses belonging to the family of Orthomyxoviridae include Influenza virus. Viruses belonging to the group of Adenoviridae include Adenovirus. [0019] Viruses belonging to the family of Arenaviridae include Lymphocytic choriomeningitis virus. Viruses belonging to the family of Paramyxoviridae include Respiratory syncytial virus. Viruses belonging to the family of Flaviviridae include Dengue virus, Hepatitis C virus, Zika virus and West Nile virus. Viruses belonging to the family of Retroviridae include Human immunodeficiency virus. Viruses belonging to the family of Caliciviridae include norovirus. Viruses belonging to the family of Picornaviridae include rhinovirus. Viruses belonging to the family of Coronaviridae include SARS-CoV, SARS-CoV2, MERS and HCoV-NL63, -OC43, -229E and HKU1. Viruses belonging to the family of Parvoviridae include bocavirus. Viruses belonging to the family of Reoviridae include Reovirus and Rotavirus. Viruses belonging to the family of Herpesviridae include Cytomegalovirus and Herpes simplex virus, such as Herpes simplex virus 1 and 2. Viruses belonging to the family of Hepadnaviridae include Hepatitis B virus. The specification teaches that in a preferred embodiment, the viral-induced disorder is a viral-induced respiratory disorder. The specification teaches that it is preferred that the virus which induces the respiratory disorder is selected from the group consisting of rhinovirus, influenza virus, parainfluenza virus, metapneumo virus, respiratory syncytial virus, adenovirus and corona virus.Therefore, hundreds, if not thousands, of disorders are encompassed.
3) The state of the prior art; 5) The level of predictability in the art;
While the state of the art is relatively high with regard to the treatment of specific viral-induced disorders, the state of the art with regard to broadly treating or preventing all viral-induced disorders is underdeveloped. For example, there is no known agent that is effective against all viral-induced disorders. The viral disease art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to the actual treatment and prevention of all viral-induced disorders in a subject, with the claimed genus of mRNAs encoding an IFNλ makes practicing the claimed invention unpredictable.
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column).
The use of mRNA for therapy is an unpredictable area of biotechnology. Baptista et al. (Pharmaceutics 2021, 13, 2090) teach that although mRNA holds great promise in therapy for numerous diseases, the main obstacle is the ability to specifically deliver it to target cells (See page 6). Baptista et al. teach one of the limitations of the use of mRNA as a therapeutic is its susceptibility to enzymatic degradation, particularly by ubiquitous RNAses in the blood and tissues (See page 6). Baptista et al. teach that in addition to RNAses, other barriers, such as the cell membrane, have to be surpassed (See page 6). Baptista et al. teach that naked mRNA does not have the necessary characteristics for its entry through the phospholipid bilayer, as this molecule has a negative charge and a large size and is hardly transported into the cell without its incorporation into a delivery system (See page 6). Baptista et al. teach that moreover, in in vivo application, intravenously administered naked mRNA is rapidly degraded and may even cause an immune response (See page 6). Baptista et al. teach that mRNA encapsulation by appropriate delivery systems is an essential requirement for this molecule to overcome those barriers (See page 6). Baptista et al. teach that numerous approaches have been used for mRNA delivery. Baptista et al. teach that physical delivery has started to be tested to increase the efficiency of mRNA uptake in vivo, but an increased cell death and limited access to target cells/tissues have been pointed out as disadvantages (See page 6). Thus, the there are many factors that have hindered the clinical progression of mRNA therapy, and one of skill in the art would not be able to predictably determine which mRNA, if any, would have therapeutic efficacy in the treatment of any given viral-induced respiratory disease or virus-induced exacerbation of a lung disease.
The use of interferon-λ in the context of viral infection is discussed by Hermant et al. (J Innate Immun 2014;6:563–574). Hermant et al. teach that one of the first studies reporting IFNλ antiviral activity in vivo demonstrated that intravaginal treatment of female mice with IFNλ prior to infection with herpes simplex virus-2 prevented virus replication in the vaginal mucosa (See page 564). Hermant et al. teach that using IFNλ receptor deficient mice, it was shown that the contribution of IFNλ to the control of viral infection greatly varied according the virus (See page 564 and table 1). For instance, studies showed no protective effect of IFNλ against infection with encephalomyocarditis virus, lymphocytic choriomeningitis virus, or vesicular stomatitis virus (See page 564). Similarly, no antiviral activity of IFNλ could be detected in mice against hepatotropic viruses, such as Rift Vallet fever, Lassa fever virus, or mutant strain of Thogoto virus (See page 564). IFNλ was found to have a modest but detectable antiviral activity in vivo against influenza virus, human metapneumovirus and severe acute respiratory syndrome coronavirus (See page 564). Additional studies carried out with influenza virus showed variable extents of protection mediated by IFNλ (See page 564). Hermant et al. teach that the contribution of IFNλ was much clearer in respiratory syncytial virus and IFNλ was shown to play a major role in the protection against rotavirus (See page 564). Thus, the antiviral activity of IFNλ depends on the virus, and it cannot be predicted which viral-induced disorders and virus-induced exacerbations of a lung disease would be amenable to treatment with the claimed mRNA encoding an IFNλ. The art supports that one of skill in the art would need guidance regarding the specific mRNA encoding an IFNλ that can be used for treating or preventing a particular viral-induced disorder or viral-induced lung exacerbation.
Given the extremely broad nature of the encompassed disorders, which have variable etiology and pathology, and the teachings of the references named above, one of skill in the art would not be able to predict the effectiveness of the encompassed mRNA encoding an IFNλ to prevent and treat each of the claimed viral-induced disorders.
Further, in vitro and animal model studies have not correlated well with in vivo clinical trial results in patients. Since the therapeutic indices of biopharmaceutical drugs can be species- and model-dependent, it is not clear that reliance on the in vitro and in vivo experimental observations, as well as the clinical experience, accurately reflects the relative ability or efficacy of the claimed methods to treat and prevent the encompassed viral-induced disorders. Regarding in vivo methods which rely on previously undescribed and generally unpredictable mechanisms, ''The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.'' In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction'' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03).''
Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the court states “[W]here there is “no indication that one skilled in [the] art would accept without question statements [as to the effects of the claimed drug products] and no evidence has been presented to demonstrate that the claimed products do have those effects,” an applicant has failed to demonstrate sufficient utility and therefore cannot establish enablement” and “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.”
6) The amount of direction or guidance provided by the inventor; 7) The existence of working examples:
The instant specification provides a working example demonstrating that prophylactic treatment with IFNλ1 mRNA reduced SARS-CoV2 and IAV virus load while Stop mRNA did not (See page 43). The specification teaches that dose dependent reduction of virus load by recombinant IFNλ1 was observed, but was lower with recombinant protein compared to mRNA treatment (See page 43). However, no other agents were administered to any other subjects with any of the encompassed viral-induced disorders or viral-induced exacerbations of a lung disease, or to animal models for any of the encompassed viral-induced disorders or viral-induced exacerbations of a lung disease. Furthermore, no administration demonstrated prevention of any encompassed viral induced disorder or viral-induced exacerbation of a lung disease. Therefore, one of skill in the art would have been required to engage in undue experimentation to first determine the structure of the mRNA encoding a particular IFNλ, then match the mRNA with the appropriate disorder that could be treated and/or prevented by the mRNA. This experimentation would require testing millions of mRNAs against hundreds of possible disorders to identify a match for therapy. This amount of experimentation would be an undue burden.
In conclusion, the claimed invention does not provide enablement for the entire scope of the rejected claims. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-14, 16-19, and 24-31 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-18 and 23-30 of copending Application No. 19/248,327 (reference application).
Both sets of claims recite a method of treating or preventing a viral-induced disorder comprising administering to a subject an effective amount of a pharmaceutical composition comprising an mRNA encoding an IFN-λ, thereby treating or preventing the viral-induced disorder. Both sets of claims recite identical dependent claims: wherein said viral-induced disorder is a viral-induced respiratory disorder; wherein the virus which causes said viral- induced respiratory disorder is selected from the group consisting of rhinovirus, influenza virus, parainfluenza virus, metapneumo virus, respiratory syncytial virus, adenovirus and coronavirus; wherein the virus which causes said viral- induced respiratory disorder is a virus which enters cells via the ACE2 receptor; wherein said virus is SARS- CoV, SARS- CoV-2 or HCoV-NL63; comprising administering the mRNA by delivery into the respiratory system of the subject; wherein said delivery into the respiratory system is via inhalation or instillation; wherein said inhalation is inhalation of an aerosol comprising said mRNA; wherein the mRNA comprises a combination of unmodified and modified nucleotides, wherein 5 to 50% of the uridine nucleotides in the mRNA and 5 to 50% of the cytidine nucleotides in the mRNA are modified uridine nucleotides and modified cytidine nucleotides, respectively; wherein said IFN-λ polypeptide is selected from the group consisting of IFN-λ1, IFN-λ2, and IFN-λ3 or a combination thereof; wherein the mRNA comprises a coding region as shown in SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 5; wherein the mRNA coding for IFNλ 1 has a sequence as shown in SEQ ID NO: 13, wherein the mRNA coding for IFN λ 2 has a sequence as shown in SEQ ID NO: 14 or wherein the mRNA coding for IFN λ 3 has a sequence as shown in SEQ ID NO: 15; further comprising administering to the subject an effective amount of an mRNA encoding a type I interferon and/or an mRNA encoding a type II interferon; wherein the type I interferon is selected from the group consisting of IFN-α, and IFN-β, and wherein the type II interferon is IFN-γ; wherein the modified uridine nucleotides are 2-thiouridine and the modified cytidine nucleotides are 5-methylcytidine; IFN-α is IFN-α16; wherein the virus is a member of the Pneumoviridae, Orthomyxoviridae, Adenoviridae, Arenaviridae, Paramyxoviridae, Flaviviridae, Retroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Parvoviridae, Reoviridae, Herpesviridae or Hepadnaviridae family; wherein the virus causing the virus-induced disorder is influenza or SARS-CoV-2; wherein the mRNA comprises 2.5% to 100% modified nucleotides; wherein the mRNA comprises 2.5 % to 100 % modified uracil (U) nucleotide, 2.5 % to 100 % modified cytosine (C) nucleotide, 2.5 % to 100 % modified guanine (G) nucleotide or 2.5 % to 100 % modified adenine (A) nucleotide; wherein said delivery is nasal delivery or lung delivery; wherein the virus is SARS-CoV-2; wherein the virus is influenza.
Both sets of claims recite a method of treating or preventing a virus-induced exacerbation of a lung disease in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an mRNA encoding an IFN-λ, thereby treating the virus induced exacerbation of the lung disease in the subject. Both sets of dependent claims recite: wherein the lung disease is asthma or chronic obstructive pulmonary disease; wherein the virus causing the virus induced exacerbation of the lung disease is influenza or SARS-CoV-2.
This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Claims 20-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 23-30 of copending Application No. 19/248,327 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims encompass a pharmaceutical composition comprising an mRNA encoding an IFNλ, wherein the IFNλ is IFNλ1, IFNλ2, IFNλ3, or a combination thereof. Both sets of claims recite that the mRNA comprises a coding region as shown in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. The difference between the instant claims and the co-pending claims is that the instant claims are drawn to a composition; however, the claims composition is required to practice the method of the co-pending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674