DETAILED ACTION
Disposition of Claims
Claims 1-5, 7-10, 12, 14, 16, and 20-22 are pending.
Examiner’s Note
All paragraph numbers, unless otherwise noted, are from the PGPub of this instant application, US20220193222A1, Published 06/23/2022.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
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Claim Objections
Claim 7 is objected to because of the following informalities: “Bunyavirus” is recited twice (lines 4 and 5); likewise, “Flavivirus” and “Togavirus” are also recited twice. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 21, and 22, and dependent claims 2-5, 7-10, 12, 14, 16, and 20 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “stabilizing” with reference to a virus in claims 1, 21, and 22 is a relative term which renders the claim indefinite. The term “stabilizing” with reference to a virus is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. At ¶[0080], a definition regarding “stable formulation” or “stable pharmaceutical formulation” is provided, but this definition only states how one can measure to test if the virus in the formulation is stable, but does not provide a numerical value or a specific marker as to how one is to determine if said formulation is “stable” or “unstable” (e.g. after storage at or below ambient temperature for X number of hours/days/weeks/months, the virus in the formulation has lost less than 1 log of activity when analyzing PFU/mL, etc.) Therefore, while the definition provided shows how one can measure different parameters of a virus, it fails to provide a specific metric to allow one to know if their formulation is, or is not, stable with respect to the virus.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 1, 21, and 22 are rejected on the grounds of being indefinite. Claims 2-5, 7-10, 12, 14, 16, and 20 are also rejected since they depend from claim 1, 21, or 22, but do not remedy these deficiencies of claim 1, 21, or 22.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites “Pertussis”, which is a bacteria, not a virus.
There are multiple recitations of diseases throughout the claim (see e.g. “Herpes”, “Hepatitis C”, “Hepatitis E”, “Eastern equine encephalitis”, etc.) that are not followed by the term “virus”.
Claim 7 has multiple items within parentheses (see e.g. “Hepadnavirus”, “Flavivirus”, and “Calcivirus”). It is unclear if the recited element within parentheses is a required element of the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites the broad recitation “Alphavirus”, and the claim also recites “Eastern equine encephalitis” (it is assumed this was meant to claim Eastern equine encephalitis virus) which is the narrower statement of the range/limitation. Similarly, “Togaviruses” are a family of viruses (family Togaviridae) while “Alphaviruses” are a genus within that larger family. “Parvoviruses” are a family of viruses (Parvoviridae) of which “adeno-associated viruses” are a species. “Hepatitis A virus” is a species of the family of “Picornaviridae” (Picornavirus). “Norwalk virus” is a species of “Calcivirus”. “Hepatitis E [virus]” is a species of “Calcivirus”. “Hepatitis C [virus]” is a species of “Flavivirus”. “Varicella zoster virus”, “Cytomegalovirus”, “Epstein-Barr virus”, “HSV1”, “HSV2”, “Kaposi’s sarcoma associated herpesvirus”, and “HHV6” are all species of “Herpesviruses”.
The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Applicant is urged to carefully identify all recitations of diseases and all species/genus instances in the claim, as there are so many instances within the large Markush group of broad followed by narrow recitations that not all have been delineated herein.
For at least these reasons, claim 7 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a formulation for stabilizing a virus at or below ambient temperature, wherein the formulation comprises:
a) a virus to be stabilized,
b) a mixture of amino acids at a total concentration of about 0.5-4%w/w,
c) a salt at about 0.05-0.1%w/w,
d) a carbohydrate at about 5% to 10%w/w,
e) a protein at about 2%w/w, and
f) water;
wherein the amino acids are each at a concentration of about 0.25% w/w to 0.5%w/w and
wherein the mixture of amino acids are selected from six of Alanine (A), Arginine (R), Asparagine (N), Aspartic Acid (D), Cysteine (C), Glutamic Acid (E), Glutamine (Q), Glycine (G), Histidine (H), Methionine (M), Proline (P), Serine (S), Threonine (T), Tyrosine (Y), Lysine (K) and Valine (V).
Further limitations on the formulation of claim 1 are wherein the formulation further comprises a seventh amino acid selected from Alanine (A), Arginine (R), Asparagine (N), Aspartic Acid (D), Glutamic Acid (E), Glutamine (Q), Glycine (G), Histidine (H), Methionine (M), Proline (P), Serine (S), Threonine (T), and Valine (V) (claim 2); wherein the formulation further comprises an eighth amino acid selected from Alanine (A), Arginine (R), Asparagine (N), Aspartic Acid (D), Glutamic Acid (E), Glutamine (Q), Glycine (G), Histidine (H), Methionine (M), Proline (P), Serine (S), Threonine (T), and Valine (V) (claim 3); wherein the formulation further comprises a ninth amino acid selected from Alanine (A), Arginine (R), Asparagine (N), Aspartic Acid (D), Glutamic Acid (E), Glutamine (Q), Glycine (G), Histidine (H), Methionine (M), Proline (P), Serine (S), Threonine (T), and Valine (V) (claim 4); wherein the formulation further comprises a tenth amino acid selected from Alanine (A), Arginine (R), Asparagine (N), Aspartic Acid (D), Glutamic Acid (E), Glutamine (Q), Glycine (G), Histidine (H), Methionine (M), Proline (P), Serine (S), Threonine (T), and Valine (V) (claim 5);
wherein the virus is selected from Adeno-associated virus (AAV), Adenovirus, Arenavirus, Alphavirus, Astrovirus, BK virus, Papovavirus, Calicivirus, Bunyavirus, Reovirus, Coronavirus, Coxsackie virus, Cytomegalovirus, Flavivirus, Filoviruses, Epstein-Barr Virus, Echovirus, Eastern equine encephalitis virus, Togaviruses, Hantavirus, Hepatitis A virus, Hepadnavirus, Norwalk virus, Varicella-Zoster virus, Retrovirus, Herpes Simplex I, Herpes Simplex II, Orthomyxovirus, Kaposi's Sarcoma associated herpes virus KSHV (HHV8), Lentivirus, Paramyxovirus, HHV7, Newcastle disease virus, Norovirus, Papillomavirus, Parvovirus, Picornavirus, Rhabdovirus, Rhinovirus, Roseolavirus (HHV-6), Rotavirus, and Poxvirus (claim 7); wherein the formulation further comprises a surfactant (claim 8); wherein the surfactant is at least one of polysorbate 20 (PS-20), polysorbate 80 (PS-80) or poloxamer 188 (F-68)(claim 9); wherein the protein is selected from at least one of albumin, recombinant proteins, cytokines, enzymes, antibodies, gelatin and soy peptone (claim 10); wherein the carbohydrate is selected from at least one of glucose, fructose, lactose, maltose, sucrose, trehalose, sorbitol, mannitol and inositol (claim 12); wherein the salt is selected from at least one of sodium chloride, potassium chloride, magnesium chloride, manganese chloride, sodium phosphate, potassium phosphate, sodium sulfate, potassium sulfate and ammonium sulfate (claim 14); and wherein the pH of is from about 3 to 9 (claim 16).
Claim 20 is drawn to a method of stabilizing a virus in solution comprising a step of suspending the virus in the formulation of claim 1.
Claim 21 is drawn to a formulation for stabilizing a virus at or below ambient temperature consisting of three amino acids, wherein the three amino acids are selected from the group consisting of glutamic acid (E), Proline (P), Serine (S), Threonine (T), wherein the three amino acids are at a total concentration of about 0.5% - 4%w/w of the formulation, and wherein the formulation further comprises:
a) a salt at about 0.05% - 0.1%w/w;
b) a carbohydrate at about 0.5% - 10%w/w;
c) a protein at about 2%w/w; and
d) water.
Claim 22 is drawn to a formulation for stabilizing a virus at or below ambient temperature comprising a first and second amino acid,
wherein the first amino acid is selected from aspartic acid (D) and qlutamic acid (E), and
wherein the second amino acid selected from threonine (T), proline (P), serine (S) and qlutamic acid (E),
wherein the first and second amino acids are at a total concentration of about 0.5% - 4%w/w of the formulation, and
wherein the formulation further comprises:
a) a salt at about 0.05% - 0.1%w/w;
b) a carbohydrate at about 0.5% - 10%w/w;
c) a protein at about 2%w/w; and
d) water.
Claim Rejections - 35 USC § 112(a); First Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 7-10, 12, 14, 16, and 20-22 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
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 .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1-5, 7-10, 12, 14, 16, and 20-22 are rejected as lacking adequate descriptive support for generating a formulation which results in the claimed function of stabilizing any virus at or below ambient temperature.
In support of the claimed genus (formulation which stabilizes any virus at or below ambient temperature), the application discloses a few examples using a specific base formulation using either Herpes Simplex virus (HSV, enveloped dsDNA virus), adeno-associated virus (AAV, non-enveloped ssDNA virus), lentivirus (enveloped, ssRNA-RT virus), or vaccinia virus (VACV, enveloped, dsDNA virus) in which the base viral stabilizing solution (VSI) is able to provide stability to the virus which is within the composition. The variables that seem ultimately critical to the solution to result in the claimed function are the viral stabilizing solution (VSI; listed as 20 mM histidine buffer, 100 mM NaCl, 5% trehalose, 2% mannitol, 2% inositol, 2% albumin, 0.25% LAlanine, 0.25% L-Arginine, 0.25% L-Asparagine, 0.25% Glutamine, 0.25% L-Glycine, 0.25% LHistidine, 0.25% Methionine, 0.25% L-Proline, 0.25% L-Serine, 0.25% L-Threonine, 0.25% LValine, 0.15% L-Tyrosine, 0.25% Aspartic Acid, 0.5% Glutamic Acid), and pH about 6.0 (¶[0119]-[0145]). Surfactants polysorbate-20, polysorbate-80, and poloxamer 188 appeared to enhance the stabilizing effect of the VSI with lentivirus (¶[0130-0131]). This base “VSI” composition was mainly tested on examples of enveloped (e.g. HSV) and non-enveloped (e.g. AAV) viruses at room temperature (25-28 C) or colder (refrigerated at 2-8C, frozen -70C), but was not tested on heat-stressed compositions (e.g. any temperature reasonably above 30C). It is not clear as to how freeze drying/lyophilization affected all different viruses, or if the virus was spray dried if the stability was affected. No other environmental variants (e.g. humidity, UV exposure, etc.) were tested for their effect on the compositions. It is not clear if there was a critical concentration of virus for each type of virus. Beyond those concentrations and elements noted in the main VSI composition, it is not clear that the breadth of components in the formulation claimed would result in the function as claimed; no derivatives or variants or mutants thereof are disclosed of any virus formulations within any other type of buffer, any other types of virus (e.g. no ssRNA or dsRNA viruses were tested), or any other types of additives such as amino acids and salts that can achieve this claimed function of “stabilizing a virus”. For instance, it is not clear that any salt, whether it be a monovalent or divalent salt, would have the same efficacy in solution as the NaCl tested. As noted in the art (Mylon SE, et. al. Langmuir. 2010 Jan 19;26(2):1035-42.; Fellowes ON. Appl Microbiol. 1966 Mar;14(2):206-11.), the salt can have critical effects on allowing viral particles to aggregate and can ultimately affect their stability during storage. As noted by Chen et. al. (Chen D, et. al. Expert Rev Vaccines. 2009 May;8(5):547-57.), instability of viral vaccines can be attributed to the instability of the proteins forming the envelope or the capsid, and all these destabilizing processes are affected by factors such as pH, buffer, salts, ionic strength, and temperature fluctuations, with enveloped particles generally being more instable than non-enveloped particles (p. 550, left col, ¶2-3). Chen further notes that excipients within viral compositions must be optimized not only due to rendering the virus more stable, but also to ensuring the resulting composition remains non-toxic and sufficiently immunogenic (p. 550, rt. col. ¶1). When focusing on one specific virus, it is noted that a variety of parameters, including amino acids, pH, polyols, sugars, and polyanions, affected the stability of viral particles (Ausar SF, et. al. Hum Vaccin. 2007 May-Jun;3(3):94-103. Epub 2007 May 15.) For instance, in Figure 1, it is clear to see that histidine causes greater aggregation over the control, while arginine prevents any particles from aggregating. While a number of examples of stable formulations have been shown with different viruses, this is with a specific formulation with specific components, and it is not clear that substitution of NaCl with another salt such as KCl will have an adverse effect, or substitution of albumin with any other protein will affect the thermostability of the composition. Thus, the application fails to provide a sufficient number of examples of species within the broadly claimed genera.
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence that any formulation claimed can still retain the ability to stabilize any virus under the conditions noted. No correlation has been made to which viral or non-viral components are critical in order to achieve the claimed stabilizing function, nor is it clear that all viruses have increased stability when stored under any type of condition (e.g. Fig. 1A shows little change in stability between the controls of HSV, lentivirus, and vaccinia virus when stored under static conditions.)
The teachings of the art also fail to indicate that, without such evidence, those in the art would have expected the full scope of the claimed formulations would confer the claimed stability. For instance, Joshi et. al. (Joshi V, et. al. Biotechnol J. 2014 Sep;9(9):1195-205. Epub 2014 May 12.; hereafter “Joshi”) highlights the routine nature of optimizing buffers, temperatures, and hold times during antibody processing to prevent aggregation of said antibody (entire document; see abstract), Joshi points out that the “underlying mechanism that results in the aggregation due to changes in buffers and salts is complex and not well understood. The complexity is compounded by our inability to definitively differentiate between the various protein stabilization mechanisms and the small free energies of stabilization of globular proteins (p. 1196, ¶ bridging cols.) However, Joshi notes that citrate buffers at pH 6 tend to have less aggregation (abstract) and that identifying the isoelectric point (pI) of the antibody can have significant effects on buffer, pH, and additive choices to help stabilize the monoclonal antibody (Mab)(p. 1196, left col., ¶2).
While the teachings of Joshi relate to antibodies, they are relevant with respect to viral formulations as well, as it is generally accepted in the art that compositions must be optimized to maintain the stability of the proteinaceous component. Live virus vaccine formulations need components within their formulations to maintain the stability of said virus; while the intended use of the claimed stabilized virus compositions is not listed, one of the main reasons one of skill in the art would want to stabilize viruses is for vaccine compositions to retain integrity, immunogenicity, and stability, especially over a period of time and over a potential range in temperatures. Each virus family and even subtype has a unique isoelectric point (pI) for mature virions and each individual virus is affected by the overall concentration of components and pH of solution in which they are found, which should be optimized not only to each viral family, but often to viral subtypes and species to maintain viral stability (See e.g. White JA, et. al. Vaccine. 2016 Jul 12;34(32):3676-83. Epub 2016 May 4.; Wiggan O, et. al. Vaccine. 2011 Oct 6;29(43):7456-62. Epub 2011 Jul 29.) For instance, there is a large difference in general stability of enveloped versus non-enveloped viruses, with the former having a lipid bilayer that generates typically less stable viruses (Kumru OS, et. al. Biologicals. 2014 Sep;42(5):237-59. Epub 2014 Jul 1.; p. 240, left col. ¶1.)
A review by Morefield (Morefield GL. AAPS J. 2011 Jun;13(2):191-200. Epub 2011 Feb 23.) notes the criticality of parameters which must be tested for each viral vaccine composition, including pH, buffer species, ionic strength, evaluation of stabilizers, interaction of antigen with non-antigen components, and monitoring stability of antigen in real time and accelerated conditions (p. 191, ¶ bridging cols.) Further, Schlehuber et. al. (Schlehuber LD, et. al. Vaccine. 2011 Jul 12;29(31):5031-9. Epub 2011 May 25.) notes that the majority of live, attenuated viral vaccines (LAV) require the careful temperature regulation from the point of manufacture through administration to preserve their stability and efficacy, and maintaining such a temperature through the “cold chain” is difficult in less developed areas or countries (p. 5031, ¶ bridging cols.) While lyophilization or spray drying increases the storage stability of a virus, said virus must normally be reconstituted before administration and often quickly loses its potency (p. 5032, rt. col. ¶2). Schlehuber notes a screening strategy to test various buffers, stabilizers, antioxidants, and chelating agents on a virus to determine the overall efficacy on viral stability (Table 1, Sect. 3.3).
Cardoso et. al. (Cardoso FMC, et. al. Acta Virol. 2017;61(3):231-239.) lists that live attenuated vaccine formulations normally consist of buffers and at least one of the two types of stabilizers: 1) protein components (including peptides, amino acids, human serum albumin, gelatin, lactoalbumin, or polygeline) or 2) sugar and sugar alcohols (e.g. sucrose, trehalose, sorbitol, mannitol, lactose.)(p. 232, rt. col., ¶1). Cardoso notes that the trend has been to utilize amino acids to prevent the use of animal byproducts, such as serum albumin, which may contain contaminants such as prions (p. 234, rt. col., ¶2). With respect to amino acids, Cardoso notes:
“Interestingly, amino acids are used in both licensed and experimental vaccines with similar frequency, about 25-30% of all vaccine type's formulations containing at least one amino acid. Glutamate, arginine, histidine and alanine are the most commonly mentioned amino acids in both licensed and experimental vaccine formulations. Most of the formulations that include amino acids are LAV, while in IN and SUB formulations the amino acid presence is reduced or they are not present at all. Amino acid mixtures are used for increasing protein solubility and stability. There are several reasons for amino acid presence in the vaccine formulations, depending on the amino acid physicochemical characteristics. For example, the histidine has antioxidant and buffering properties, by scavenging HO- radicals in solutions and by controlling pH and stabilizing non-covalent interaction of solid state proteins. Another interesting amino acid is arginine, which is widely known for preventing protein aggregation by interacting with aromatic and charged protein residues.” (p. 236, left col., ¶2)
The amino acid physiochemical characteristics are important to note, as not only are there different types of amino acids with different isoelectric points (pI), sizes, and hydrophobicities, but amino acids also differ in solubility depending on the salt concentration and ionic strength of the solution (Needham 1970). An excess of amino acids in solution may generate micelle-like structures, which may or may not affect the stability of the virus utilized in the mixture. While the application has been narrowed to select only six amino acids in the composition, the group of amino acids from which one can select includes 13 different amino acids which can result in a large number of possible permutations within the amino acid mixture. In applicant’s response, they note the surprising results of the composition, but these surprising results only appear to happen with a specific set and concentration of amino acids, and definitely not the breadth of possible amino acid compositions presently claimed.
Thus, in view of the above, there would have been significant uncertainty as to which specific components within the resulting formulations for which viruses would be able to maintain the claimed function of stabilizing the virus, especially over the range of storage conditions claimed. In view of this uncertainty and the lack of sufficient examples of the claimed genera, the claims are rejected for lack of adequate written description support.
Claims 1-5, 7-10, 12, 14, 16, and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a specific viral stabilizing solution (VSI solution, ¶[0120]) when used with herpes simplex virus (HSV), adeno-associated virus (AAV), lentivirus, and vaccinia virus, at specific concentrations, does not reasonably provide enablement for any composition comprising any of the amino acids, viruses, and other reagents claimed at any of the percentages or weights claimed, insomuch that said resulting formulation stabilizes the virus in said solution at or below ambient temperature. 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/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a formulation for stabilizing a virus at or below ambient temperature, wherein the formulation comprises a virus, a mixture of 6 amino acids selected from 16 known amino acids, a salt, a carbohydrate, a protein, all at specific % w/w and water. The virus may be any virus, including any enveloped or non-enveloped virus with any type of genome (e.g. DNA or RNA, single-stranded or double-stranded, positive sense or negative sense.) The “virus” is not noted as being in any specific state, and may reasonably be interpreted as being “live” or “killed”, wherein “live” virus may be fully virulent, attenuated, or replication defective. As set forth supra, it is unclear how one in the art is to determine if the formulation is “stable” or “unstable” with respect to the virus, as a specific metric as to how one is to measure “stability” has not been provided. The breadth of the other components is not narrowed until further dependent claims, and can include any salt at the provided concentration, any carbohydrate at the provided concentration, and any protein at the provided concentration. “Water” can also be any type of water (e.g. purified, sterile, deionized water, etc.)
State of the prior art/Predictability of the art. The state of the art has been summarized supra with respect to the written description rejection, and notes the criticality of parameters in each component in any viral formulations must be empirically tested to ensure that they are non-toxic, immunogenic, and stable. As the intended use of the formulation has not been claimed (e.g. it is unclear if this formulation is for laboratory use, clinical use, or both), nor has the form of the virus in the formulation been claimed, it is further unclear how one would determine if the formulation is “stable” over what specific period of time.
Working examples. The working examples disclosed in the specification have been elaborated upon supra with respect to the written description rejection. As noted supra, the application discloses a few examples using a specific base formulation using either Herpes Simplex virus (HSV, enveloped dsDNA virus), adeno-associated virus (AAV, non-enveloped ssDNA virus), lentivirus (enveloped, ssRNA-RT virus), or vaccinia virus (VACV, enveloped, dsDNA virus) in which the base viral stabilizing solution (VSI) is able to provide stability to the virus which is within the composition. The variables that seem ultimately critical to the solution to result in the claimed function are the viral stabilizing solution (“VSI”; listed as 20 mM histidine buffer, 100 mM NaCl, 5% trehalose, 2% mannitol, 2% inositol, 2% albumin, 0.25% LAlanine, 0.25% L-Arginine, 0.25% L-Asparagine, 0.25% Glutamine, 0.25% L-Glycine, 0.25% LHistidine, 0.25% Methionine, 0.25% L-Proline, 0.25% L-Serine, 0.25% L-Threonine, 0.25% LValine, 0.15% L-Tyrosine, 0.25% Aspartic Acid, 0.5% Glutamic Acid), and pH about 6.0 (¶[0119]-[0145]). Surfactants polysorbate-20, polysorbate-80, and poloxamer 188 appeared to enhance the stabilizing effect of the VSI with lentivirus (¶[0130-0131]). This base “VSI” composition was mainly tested on examples of enveloped (e.g. HSV) and non-enveloped (e.g. AAV) viruses at room temperature (25-28 C) or colder (refrigerated at 2-8C, frozen -70C), but was not tested on heat-stressed compositions (e.g. any temperature reasonably above 30C). It is not clear as to how freeze drying/lyophilization affected all different viruses, or if the virus was spray dried if the stability was affected. No other environmental variants (e.g. humidity, UV exposure, etc.) were tested for their effect on the compositions. It is not clear if there was a critical concentration of virus for each type of virus. Beyond those concentrations and elements noted in the main VSI composition, it is not clear that the breadth of components in the formulation claimed would result in the function as claimed; no derivatives or variants or mutants thereof are disclosed of any virus formulations within any other type of buffer, any other types of virus (e.g. no ssRNA or dsRNA viruses were tested), or any other types of additives such as amino acids and salts that can achieve this claimed function of “stabilizing a virus”.
Guidance in the specification. The specification provides guidance towards the use of a specific “VSI” formulation with specific viral species, namely live herpes simplex virus (HSV), Vaccinia virus, adeno-associated virus (AAV), and lentivirus (¶[0121]), for a time period of 30 days (¶[0132]). It is not clear what specific types of these viruses were used (e.g. it is unclear if HSV-1 or HSV-2 was used and what strain or subtype for each of the viruses, such as AAV-1, AAV-2, AAV-3, etc.)
Amount of experimentation necessary. Additional research is required in order to determine how effective the breath of the formulations claimed would be on providing stability to any virus in any of the claimed solutions for any period of time at the temperatures noted.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the breadth of the limitations or genera claimed, namely the viruses, salts, proteins, carbohydrates, water, and amino acids, is so large, and the criticality of parameters for each type of virus have not been delineated, making testing of possible permutations of possible formulations an extremely burdensome process to determine which formulations would result in the functions claimed.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claims 1-5, 7-10, 12, 14, 16, and 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sediq et. al. (WO2018210804A1, Pub. 11/22/2018; Priority 05/15/2017; hereafter “Sediq”.)
The Prior Art:
Sediq teaches compositions comprising viruses, wherein said compositions increase the storage or shelf life stability of the virus within said composition (entire document; see abstract.) Sediq teaches the composition is comprising a) an enveloped virus; b) a buffer; and c) a sulfate salt at a concentration of about 5 mM to about 300 mM, wherein said composition has a pH of about 6.0 to about 8.5 (reference claim 1; instant claim 16). Sediq teaches the sulfate salt is selected from the group consisting of sodium sulfate, potassium sulfate, magnesium sulfate and an ammonium sulfate (reference claims 13-15; instant claim 14). Sediq teaches wherein the composition further comprises a sugar, sugar alcohol and/or polyol (reference claim 20) such as glycerol in an amount between 1 and 6% w/w (reference claims 21-23) or sucrose in a concentration between 1-10% w/w (reference claims 24-25; instant claim 12). Sediq teaches that the composition may comprise one or more auxiliary agents, such as one or more amino acids, adjuvants, diluents, stabilizers, carriers, or additives (p. 29, ¶2). The amino acid is preferably selected from the group of arginine, glycine, alanine, lysine, proline, histidine, glutamate, glutamic acid and aspartic acid or any combination thereof, and is preferably an L-isomer not encoded by the virus comprised within the composition, and is present at a concentration of about 0.1-10% (pp. 30-31, ¶ bridging pages; instant claims 1, 2-5, 21.) The viscosity enhancer may be gelatin in a range of about 0.1-10% w/w (p. 32, ¶2; instant claim 10). Therefore, Sediq teaches a composition for viral storage and stability comprising a virus, amino acids, protein, salt, and a carbohydrate, all at the claimed concentrations of instant claim 1. Sediq teaches a method of making said solutions starting with the “Examples” at p. 38 (instant claim 20), and teaches generation of compositions comprising enveloped viruses, such as poxviruses, influenza viruses, respiratory syncytial virus, and herpes simplex virus (reference claim 3; instant claim 7). Said composition may further comprise surfactants (p. 30, ¶2; instant claim 8) such as polysorbate 20 or polysorbate 80 (p. 30, ¶3; instant claim 9).
For at least these reasons, Sediq teaches the limitations of instant claims 1-5, 7-10, 12, 14, 16, and 20-22, and anticipates the instant invention.
Conclusion
No claims are allowed.
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/RACHEL B GILL/Primary Examiner, Art Unit 1671