DETAILED ACTION
Disposition of Claims
Claims 1-5, 9, 20, 27-28, 30, 33-34, and 36-43 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230310568A1, Published 10/05/2023.
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.
Of note, there is not an attorney of record on file due to a lack of an official power of attorney of record. While a customer number has been provided on the ADS submitted 02/16/2023, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/10/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists 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).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology (e.g. “inter alia”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See ¶[0076] “http://www.ncbi.nlm.nih.gov/” ; ¶[0186] “https://doi.org/10.1128/JVI.00072-13” ; ¶[0204] “https://doi.org/10.1128/mBio.00036-17” .
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, 9, 20, 27-28, 30, 33-34, and 36-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a wild-type arenavirus glycoprotein (GP) and methods of natural infection by arenavirus without significantly more. The claims recite a “recombinant” arenavirus glycoprotein comprising a glycoprotein ectodomain and a trimerization domain. This judicial exception is not integrated into a practical application because while the claim uses “recombinant” to insinuate the “hand-of-man” in the glycoprotein (GP), the structural elements recited in the claim (e.g. an ectodomain and trimerization domain) are native parts of a wild-type GP from arenavirus, and viruses are known to recombine naturally in nature. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no elements to show how said GP was distinguished from the wild-type form of the glycoprotein (e.g. through the use of an ectodomain or a trimerization domain that is heterologous to GP, through the use of non-wild-type GP sequences, additional non-native tags, etc.). Additional dependent claims also read on elements which occur in native, wild-type GP, such as a protease cleavage site between GP1 and GP2. The cleavage site is recognized by the host cell protease site 1 protease (S1P), also known as subtilisin-kexin-isozyme-1 (SKI-1/S1P), wherein said site occurs at a specific, conserved amino acid motif located between GP1 and GP2, generally around amino acids 262–263 (in some strains reported as a 9-amino-acid stretch containing RRLA). The native form of the LCMV GP precursor comprises a 58-amino acid long stable signal peptide (SSP) at its N-terminus, and is essential for the maturation and proteolytic cleavage of GP-C into its functional subunits (GP1 and GP2) by the SKI-1/S1P protease. The native wild-type GP forms a trimer, and said GP is encoded by the nucleic acid genome of the arenavirus. The art has shown that specific strains of arenaviruses, such as LCMV, comprise GP1 and GP2 sequences that are more likely to form stable complexes than others, such as the high affinity variant Clone 13, so these may be considered “stabilized” GP. The “cell” comprising said nucleic acid reads on a natural arenavirus-infected cell, and the “vaccine” compositions do not amount to significantly more as the “pharmaceutically acceptable carrier” reads on water (¶[0156]), which does not markedly or significantly alter the arenavirus GP. The methods of “vaccination” are recited at a high level of generality and read upon natural infection from arenavirus, as the routes of administration, the amount administered, and the composition administered all read upon natural arenaviruses and methods of natural acquisition. The methods of “detection” are recited at a high level of generality and read upon a natural correlation (e.g. native antibodies binding to arenavirus GP) and do not further comprise an active step to utilize the information regarding the natural correlation (e.g. delivering an antiviral, etc.)
One suggestion to overcome this rejection is to incorporate limitations or elements which are heterologous to the arenavirus GP, or to use non-naturally occurring sequences for said arenavirus GP, or to ensure the GP trimer compositions comprise elements that significantly alter the GP (e.g. adjuvants). The method claims can be drawn to delivery of patent-eligible compositions, and/or comprise additional, specific steps within the method that would not allow the reasonable interpretation of that method to read upon natural infection (e.g. specific methods of delivery, specific amounts of antigen delivered, etc.) Additionally, applicant is free to argue that said GP is drawn to patent-eligible subject matter.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 30 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). It is suggested these claims be amended to read upon “…an isolated cell…” in order to overcome this rejection.
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.
Claim 1 and dependent claims 2-5, 9, 20, 27-28, 30, 33-34, and 36-43 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.
Claim 1 is drawn to a recombinant arenavirus glycoprotein comprising an arenavirus glycoprotein ectodomain and a trimerization domain. However, it is unclear from the wording of the claim if the recombinant arenavirus glycoprotein contributes only to the glycoprotein ectodomain, the trimerization domain, or both, as a native arenavirus glycoprotein (GP) comprises both an ectodomain and a trimerization domain, wherein the trimerization domain is essential for forming the functional, tripartite spike on the viral surface. As the GP is claimed to be “recombinant” without providing actual structural characteristics as to how said GP is engineered, the claim is rejected on the grounds of being indefinite.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 2-5, 9, 20, 27-28, 30, 33-34, and 36-43 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
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 recombinant arenavirus glycoprotein comprising an arenavirus glycoprotein ectodomain and a trimerization domain.
Further limitations on the recombinant arenavirus glycoprotein of claim 1 are wherein said ectodomain comprises an arenavirus GP1/GP2 protein, wherein said arenavirus GP1/GP2 protein comprises a GP1 domain and a GP2 domain (claim 2), wherein the C-terminus of the GP1 domain is bound to the N-terminus of the GP2 domain, and wherein the trimerization domain is bound to the C-terminus of said GP2 domain (claim 3), wherein said ectodomain further comprises a protease cleavage site, wherein said protease cleavage site is located between said GP1 domain and said GP2 domain (claim 4), wherein said arenavirus GP1/GP2 protein is a stabilized arenavirus GP1/GP2 protein (claim 5), wherein said trimerization domain is covalently bound to said C-terminus of said GP2 domain though a peptide linker (claim 9), wherein said ectodomain further comprises a signal peptide, wherein said signal peptide is covalently bound to the N-terminus of the GP1 domain (claim 20); an isolated nucleic acid encoding the recombinant arenavirus glycoprotein of claim 1 (claim 28); an isolated cell comprising the recombinant arenavirus glycoprotein of claim 1 (claim 30); and a vaccine composition comprising the recombinant arenavirus glycoprotein of claim 1 and a pharmaceutically acceptable excipient (claim 33).
Claim 27 is drawn to a glycoprotein trimer, comprising three of the recombinant arenavirus glycoproteins of claim 1, wherein said three recombinant arenavirus glycoproteins are bound by non-covalent attachment of the trimerization domains.
Further limitations on the glycoprotein trimer are a vaccine composition comprising the glycoprotein trimer of claim 27 and a pharmaceutically acceptable excipient (claim 34).
Claims 36 and 37 are drawn to a method of treating or preventing a viral disease in a subject in need of such treatment or prevention, said method comprising administering a therapeutically or prophylactically effective amount of the recombinant arenavirus glycoprotein of claim 1 (claim 36) or the glycoprotein trimer of claim 27 (claim 37) to said subject.
Further limitations on the method of claim 36 are wherein said viral disease is caused by Lymphocytic choriomeningitis virus (LCMV), Junin virus, Machupo virus, Lassa virus, Guanarito virus, Sabia virus, Chapare virus, Whitewater Arroyo virus, or Lujo virus (claim 38).
Claims 39 and 40 are drawn to a method for immunizing a subject susceptible to a viral disease, comprising administering the recombinant arenavirus glycoprotein of claim 1 (claim 39) or the glycoprotein trimer of claim 27 (claim 40) to a subject under conditions such that antibodies directed to said arenavirus glycoprotein or a fragment thereof (claim 39) or said glycoprotein trimer or fragment thereof (claim 40) are produced.
Claim 41 is drawn to a method of diagnosing arenavirus infection in a subject, the method comprising: (a) contacting a biological sample obtained from the subject with the recombinant arenavirus glycoprotein of claim 1, and (b) detecting binding of one or more antibodies to said recombinant arenavirus glycoprotein, thereby diagnosing arenavirus infection in said subject.
Claim 42 is drawn to a method of diagnosing arenavirus infection in a subject, the method comprising: (a) contacting a biological sample obtained from the subject with the glycoprotein trimer of claim 27, and (b) detecting binding of one or more antibodies to said glycoprotein trimer, thereby diagnosing arenavirus infection in said subject.
Claim 43 is drawn to a method for evaluating effectiveness of an arenavirus vaccine in a subject, the method comprising: (a) contacting a biological sample from a subject who has been administered with the vaccine composition of claim 33, (b) detecting antibodies in the biological sample that bind to the recombinant arenavirus glycoprotein, and (c) performing quantitative and qualitative analysis of the antibodies detected in the biological sample, thereby evaluating effectiveness of the arenavirus vaccine in the subject.
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 28 and 30 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 an isolated or purified nucleic acid or host cell], does not reasonably provide enablement for said non-isolated nucleic acid or host cell which reads upon a transgenic animal or a transgene therein. 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. Applicant broadly claims a host cell and nucleic acid which encodes the arenavirus glycoprotein. Under broadest reasonable interpretation, the claims read on a cell within a transgenic animal or a transgene therein, given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
State of the prior art/Predictability of the art. With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill in the art could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene and possible silencing of host genes, which result in undesirable phenotypes and/or additional health issues in the animal. The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene in the host. Viral vectors, such as Adeno-associated virus (AAV), adenovirus (AdV), and lentiviral/retroviral vectors, can transfer larger amounts of genetic information to a host, but some vectors cannot carry all the required genetic structures for proper expression (e.g. entire gene plus extensive regulatory elements) and certain viral vectors can cause uncontrolled, random integration, which increases the risk of tumorigenesis and inconsistent expression. (See e.g. National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Food and Nutrition Board; Board on Agriculture and Natural Resources; Committee on Heritable Genetic Modification in Food Animals. Heritable Genetic Modification in Food Animals. Washington (DC): National Academies Press (US); 2025 Apr 23. 3, Potential Hazards to Animals and Consumers.; Park F. Physiol Genomics. 2007 Oct 22;31(2):159-73. Epub 2007 Aug 7.; Shakweer WME, et. al. J Genet Eng Biotechnol. 2023 May 9;21(1):55.) Therefore, the field of transgenics was and remains highly unpredictable.
Working examples/Guidance in the Specification. No working example of a transgenic animal is disclosed in the specification. The specification provides guidance towards the generation and use of an isolated/purified nucleic acid and isolated host cells.
Amount of experimentation necessary. At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to clarify that the nucleic acid and host cell is not within a transgenic animal by utilizing the term "isolated" before the recitation of said nucleic acid and host cell. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use the transgenes and transgenic animals commensurate in scope with the claimed invention with a reasonable expectation of success. Thus, the claims are rejected here.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claims 1-5, 9, 20, 27-28, 30, 33-34, and 36-43 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 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, 9, 20, 27-28, 30, 33-34, and 36-43 are rejected as lacking adequate descriptive support for generating any recombinant arenavirus-derived glycoprotein which comprises any glycoprotein from any source and any trimerization domain from any source, especially any glycoproteins which results in the functional ability to form trimers and be useful against any viral disease, useful for detecting any arenavirus infection, or for evaluating the effectiveness of any arenavirus vaccine in any subject.
In support of the claimed genera (any ectodomain from any arenavirus glycoprotein source, any trimerization domain from any source), the application discloses one example in which the GP from the arenavirus Lassa virus (LASV) was in either its native unmodified sequence or wherein the GP1/GP2 of LASV were mutated to stabilize the GP in its prefusion conformation (GPCysR4; SEQ ID NO:3) and then fused to a heterologous trimerization domain (1NOG trimerization domain, a trimerization domain identified from Thermoplasma acidophilum; SEQ ID NO: 5). Examples 1-2 starting at ¶[0304] shows the fusion of the ectodomain of the LASV glycoprotein (SEQ ID NO:3) with a heterologous C-terminal trimerization domain (1NOG, SEQ ID NO:3) gave rise to the construct GPCysR4-TD (SEQ ID NO:1). While this construct was able to form trimers at about 90% capacity (¶[0307]), a more homogeneous sample of close to 100% trimer products was desired; thus an additional heterologous C-terminal sortase motif (LPETG) was utilized (¶[0308]) along with a flexible glycine linker (¶[0308]). The sortase motif (LPETG; SEQ ID NO:15) allowed for covalent joining with separately produced NOG using the sortase enzyme from Staphylococcus aureus (Example 3 at ¶[0309]). At Example 4, prophetic examples of how the GP trimers would be optimized and tested for their immunogenic status was provided, but it does not appear as though said trimers encountered said immunogenic/antigenic testing. The LASV GPCysR4-TD of Example 1 was tested against anti-Lassa virus antibody 37.2D to determine if known neutralizing, prefusion recognizing antibodies could detect the trimers formed, and said antigens bound to the constructs generated (Fig. 3B). The constructs with the additional LPETG sortase motif were not tested for antigenicity. None of the constructs were utilized as immunogenic compositions where they were delivered in vivo to any human or animal model, and no challenge studies were performed. No other constructs were generated which fall under the breadth of the claimed invention (e.g. no other non-LASV ectodomains were joined to any trimerization domains, no other arenavirus ectodomain constructs (e.g. only GP1 or only GP2) were studied joined to any native or non-native trimerization domain.) The constructs were not tested against any other arenavirus antibodies, nor were the constructs tested for their ability to elicit therapeutic results against any arenavirus or any other virus. No arenavirus vaccine recipients had any biological sample tested with any of the claimed constructs to determine the effectiveness of said arenavirus vaccine. No detection of any arenavirus infection of any type from any source with any of the constructs was performed. Thus, the application fails to provide sufficient examples of species within the claimed genera.
Further, while the claims provide both a structure (arenavirus-derived GP with ectodomain and trimerization domain) and a function (ability to form trimers, ability to be useful in immunological methods), the application fails to draw any correlation between the two. In other words, there is no evidence that any ectodomain from any arenavirus can be fused to any trimerization domain and still formulate trimers that are therapeutically relevant to homologous and/or heterologous arenaviruses, or any other virus. Moreover, no correlation has been made to which sequences, mutations, heterologous tags/domains, or order of domains are required in order to achieve the claimed function of formulating the trimers which are useful immunologically.
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 engineered glycoprotein construct would confer the claimed structural conformation (e.g. trimer) and immunogenicity. For example, a search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, et. al. Science. 1990 Mar16;247(4948):1306-10; See page 1306). The art also shows that single amino acid mutations in the antibodies can greatly affect the ability of said antibody to bind to its target antigen (Winkler K, et. al. J Immunol. 2000 Oct 15;165(8):4505-14.; See also Kussie PH, et. al. J Immunol. 1994 Jan 1;152(1):146-52.) With respect to trimerization domains fused to heterologous proteins, there are key issues that affect the formation of trimers, such as the inherent structural instability of the target protein, immunological and safety concerns, production and folding hurdles, and technical/design limitations. With respect to structural instability, there can be post-fusion refolding, wherein soluble viral fusion proteins (e.g., RSV F, HIV Env) are inherently metastable and often revert to a stable post-fusion conformation even when a trimerization domain is added; premature destabilization, wherein the added heterologous domain can actually destabilize the desired prefusion conformation, leading to opening or unfolding of the trimer during storage (e.g., 4 °C storage of RSV F-foldon), or “breathing” or misfolding issues, wherein despite the presence of a trimerization domain, the protein may not adopt a single, native-like, homogeneous trimer, resulting in a mixture of monomers, dimers, and misfolded species (Lima DB, et. al. Nat Protoc. 2018 Mar;13(3):431-458. Epub 2018 Feb 1.) With respect to immunological concerns, the foldon or other trimerization domain may itself be immunogenic and can introduce strong non-neutralizing antibody responses against themselves that can limit the effectiveness of repeated immunizations or can inhibit the production of neutralizing antibodies against the target protein (Bakkers MJG, et. al. Nat Microbiol. 2024 Dec;9(12):3254-3267. Epub 2024 Nov 20.). With respect to production and folding issues, known issues include low yield of fusion proteins in expression systems, wherein proteins with heterologous domains may express at low levels, or accumulate as insoluble inclusion bodies, particularly in E. coli systems. Further, if the target protein relies on co-translational folding or specific chaperones not present in the host system, the added domain cannot compensate, resulting in poor folding. The level of glycosylation can vary significantly depending on the expression cell line and the protein itself, which can interfere with the structural homogeneity of the trimer (Lu Y, et. al. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):125-30. Epub 2013 Dec 16.) With respect to technical and design limitations, there may be steric hindrance/occlusion, wherein the added domain may sterically block access to key epitopes on the target protein, preventing desired antibody binding. If the heterologous domains utilize improper linking agents, such as the linker connecting the target protein to the trimerization domain may be too short, too long, or too rigid, this can negatively affect the ability of the monomers to properly align into a trimer (Caradonna TM, et. al. NPJ Vaccines. 2021 Dec 17;6(1):154.) These results highlight the pitfalls in attempting to describe a protein functionally to known structural characteristics.
Thus, in view of the above, there would have been significant uncertainty as to which arenavirus-based glycoprotein constructs could be generated, and there would be even further uncertainty which of those glycoprotein constructs would confer the additional claimed functions of formulating immunologically relevant trimers. 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, 9, 20, 27-28, 30, 33-34, and 36-43 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 the generation of the LASV GP ectodomain-1NOG trimerization domain constructs GPCysR4-1NOG/GPCysR4-TD and GPCysR4-LPXTG/GPCysR4-LPXTG-TD , does not reasonably provide enablement for any arenavirus-derived recombinant glycoprotein comprising any arenavirus ectodomain or any trimerization domain, or the ability of said constructs to form immunologically relevant trimers useful for vaccine or detection methods. 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 recombinant arenavirus glycoprotein comprising an arenavirus glycoprotein ectodomain and a trimerization domain. As set forth in the 35 USC 112b rejections supra, it is unclear as to what parts are heterologous or homologous to the arenavirus ectodomain, so under broadest reasonable interpretations, the protein could comprise an arenavirus glycoprotein ectodomain from one arenavirus, a trimerization domain from the same or a heterologous arenavirus, or the trimerization domain may be from a non-arenavirus source altogether. Further claims are drawn to wherein the glycoprotein formulates a homotrimer, and wherein either the glycoprotein or the trimer are used in methods to treat or prevent or to immunize against any viral disease. Note that the “viral disease” is not only restricted to those caused by arenaviruses, and can reasonably be interpreted to treat a viral disease caused by any virus in any subject. Further claims are drawn to either the glycoprotein or homotrimer used in a method of detecting any arenavirus infection in any subject; neither the arenavirus nor the subject were limited to any specific subset, such as detection of only LCMV or only LASV infection. Finally, the glycoprotein may be used in a method to determine the effectiveness of any arenavirus vaccine; again, the vaccine is broadly against any arenavirus of any format.
State of the prior art/Predictability of the art. “Arenavirus” is a bi- or trisegmented ambisense RNA virus that is a member of the family Arenaviridae, wherein the family includes five genera (Antennavirus, Hartmanivirus, Innmovirus, Mammarenavirus, and Reptarenavirus). These viruses infect fish (antennaviruses), snakes (hartmaniviruses and reptarenaviruses), mammals (mammarenaviruses), and unknown hosts (innmoviruses). The Mammarenavirus genus of the Arenaviridae family comprises a diverse group of enveloped, negative-sense single-stranded RNA viruses and can be divided into two categories, Old-World (OW) or New-World (NW), based on phylogenetic differences and geographical distribution. OW arenaviruses are those that circulate in Africa, Asia and Europe, whereas those classified as NW circulate in the Americas. Various species of rodents are the natural reservoirs for these viruses with endemicity dependent on the species’ indigenous location. Several viruses in this family are pathogenic in humans and are causative agents of viral hemorrhagic fevers (Pennington HN, et. al. Biosci Rep. 2022 Feb 25;42(2):BSR20211930.).
The segmented arenavirus genome consists of small (S) and large (L) segments. The S-segment encodes the nucleoprotein (NP) and glycoprotein precursor (GPC). GPC is cleaved during post-translational modification into a stable signal peptide (SSP), GP1, and GP2 to form a trimer on the viral membrane. Entry of arenaviruses such as LCMV or Lassa virus (LASV) into the host cell is mediated by the GPC, which is the only protein located on the viral surface and comprises three subunits: glycoprotein 1 (GP1), glycoprotein 2 (GP2), and a stable signal peptide (SSP). The GPC is a class one viral fusion protein, akin to those found in viruses such as human immunodeficiency virus (HIV), influenza, Ebola virus (EBOV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These viruses are enveloped and utilize membrane fusion to deliver their genetic material to the host cell. The receptor-binding subunit, GP1, first engages with a host cell receptor then undergoes a unique receptor switch upon delivery to the late endosome. The acidic pH and change in receptor result in the dissociation of GP1, exposing the fusion subunit, GP2, such that fusion can occur. These events ultimately lead to the formation of a fusion pore so that the arenavirus genetic material is released into the host cell. Interestingly, the mature GPC retains its SSP as a third subunit—a feature that is unique to arenaviruses. (Pennington et. al.; abstract.)
Arenavirus vaccine development is currently focused on overcoming the lack of approved vaccines for highly pathogenic, rodent-borne arenaviruses like Lassa (LASV) and Junin (JUNV). While no FDA-licensed vaccines exist for most human-pathogenic arenaviruses, significant progress has been made using advanced platforms, with several candidates for Lassa fever in preclinical and Phase I clinical trials, and one vaccine (Candid #1) approved in Argentina for Junin virus. There are currently no approved vaccines or specific therapeutics available for human lymphocytic choriomeningitis virus (LCMV) infection, a pathogen that causes serious illness in immunocompromised individuals and birth defects in developing fetuses. However, the state of LCMV vaccine development at the time of filing was active in the pre-clinical and research phases, focusing on using LCMV as a vector to deliver heterologous pathogenic material to a host in order to treat cancer and inhibit other infections (Flatz L, et. al. Nat Med. 2010 Mar;16(3):339-45. Epub 2010 Feb 7.)
Much of arenavirus vaccine development has focused on the GPC trimer, as it is a target of neutralizing antibodies and T-cell immunity induced by viral infection or vaccination. LASV GPC-specific non-neutralizing antibodies have also been suggested to contribute to protection from Lassa fever (LF). Since the induction of humoral and cell-mediated immunity is critical for effective vaccines, GPC has been engineered in various approaches as a pivotal element in vaccine development. Several vaccine candidates against LF have been developed. Three vaccine candidates, the recombinant vesicular stomatitis virus (VSV) expressing LASV GPC (rVSV∆G LASV-GPC), the recombinant measles virus expressing LASV GPC and NP (MV LASV), and a DNA vaccine encoding the LASV GPC gene (INO-4500) have been evaluated for their safety and efficacy in phase 1 clinical trials. In comparison to LF, other arenavirus diseases have lagged in vaccine development. Even the vaccine for Argentine hemorrhagic fever (AHF) caused by JUNV, Candid#1, has not been approved by the FDA due to concerns about the risks of residual virulence and reversion to pathogenicity (Saito T, et. al. Vaccines (Basel). 2023 Mar 13;11(3):635.)
Working examples. The working examples disclosed in the specification were detailed supra with respect to the written description rejection. Briefly, two LASV-based glycoprotein constructs were engineered and tested, LASV GP ectodomain-1NOG trimerization domain constructs GPCysR4-1NOG and GPCysR4-LPXTG, wherein the latter was developed to further stabilize the formation of trimers of the GPCysR4-1NOG construct. Only the purified GPCysR4-1NOG in trimeric formation (Example 2 at ¶[0306]) was tested for antigenicity against known neutralizing antibodies against LASV, namely 37.2D that only recognizes the prefusion LASV GP trimer. No working examples where any nucleic acid, protein, or protein complex delivered to an in vivo subject were provided for to determine any immune response elicitation, no challenge studies against LASV or any other arenavirus or other viral infection was performed to see if these engineered glycoproteins could inhibit any viral disease. No known arenavirus vaccine was tested for efficacy using these constructs as markers for the presence of antibodies. No samples from active arenavirus infections were tested using these glycoproteins or constructs thereof to determine if said constructs could detect any infection.
Guidance in the specification. The specification provides guidance towards generation of the LASV GP ectodomain-1NOG trimerization domain constructs GPCysR4-1NOG and GPCysR4-LPXTG. As detailed supra with respect to the written description rejection, while prophetic examples as to how said construct may be used, much experimentation is still necessary to determine if said constructs would be clinically useful for the treatment of LASV or any other viral disease or infection, as there are known issues with the use of heterologous trimerization domains in chimeric protein constructs for vaccine development. No guidance was provided for in the specification to use the LASV trimerization domain with any other arenavirus ectodomain, no guidance was provided for any other non-LASV ectodomain to be used with any other trimerization domain, whether it was from LASV, another arenavirus, or a non-arenavirus trimerization domain. No in vivo was performed to determine the efficacy of said constructs with respect to eliciting any therapeutic or prophylactic immune response against any homologous or heterologous arenavirus or virus in general. No testing of active arenavirus infections or arenavirus-vaccinated individuals was performed to determine if said constructs would be useful in such settings.
Amount of experimentation necessary. Additional research is required in order to determine how to generate the breadth of arenavirus-based glycoprotein constructs. Additional research is required in order to determine how effective the breadth of the arenavirus-based glycoprotein constructs would be in the construction of trimers, as clearly the specification has shown that the GPCysR4-1NOG constructs failed to produce 100% trimers and required the LPETG domain for further stabilization. Even further, additional research is required to determine the effectiveness of the breadth of arenavirus-based glycoprotein constructs in the methods as claimed, especially for use in vaccination regimens against any viral disease, for detection of any viral infection, or for detection of any immune response elicited by any arenavirus vaccine.
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, due to the breadth and indefinite nature of the claims, and the multiple potential genera which are reasonably encompassed by the claims (e.g. portion of arenavirus in glycoprotein, ectodomain component, trimerization domain, homotrimers, arenavirus capable of treatment/detection by said glycoprotein, viral diseases capable of treatment by said glycoprotein, etc.) the amount of experimentation and the uncertainty in the art makes the necessary experimentation required undue in order to enable the breadth of the claims.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products and 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, 9, 20, 27-28, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eschli et. al. (Eschli B, et. al. J Virol. 2006 Jun;80(12):5897-907.; hereafter “Eschli”.)
The Prior Art
Eschli teaches generating a construct comprising the arenavirus LCMV glycoprotein (GP), wherein the GP ectodomain comprising the GP1 and GP2 subunits was fused C-terminally to the trimeric motif of fibritin (entire document; see abstract; instant claims 1-2). Eschli teaches that the GP1/GP2 protein comprises, in the N- to C- terminal direction, a signal peptide, the GP1 domain, a cleavage site, and the GP2 domain, wherein the GP2 domain was fused at its C-terminus to the fibritin trimerization sequence, and the native SKI-1/S1P cleavage site was mutated and removed via a point mutation (Fig. 2; “Materials and Methods: Generation of the GP fibritin fusion construct.”, p. 5898; instant claims 3-4, 9, 20). Eschli teaches the GP has a 58-amino acid signal peptide that even after cleavage remains with the GP construct (pp. 5897-8, ¶ bridging pages; Fig. 4; instant claim 20). Said construct formed trimers (Fig. 4; instant claim 27) which resembles the GP spike in its preactivated prefusion state (p. 5904, left col., ¶2; instant claim 5.) HEK293T cells were stably transfected with the nucleic acid constructs and produced the GP-fibritin (GPfib) protein (Fig. 4; instant claims 28, 30).
For at least these reasons, Eschli teaches the limitations of instant claims 1-5, 9, 20, 27-28, and 30, and anticipates the invention encompassed by said claims.
Claims 1-5, 9, 20, 27-28, 30, 33-34, and 36-43 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Jasny et. al. (US20210260178A1; Priority 06/27/2018; hereafter “Jasny”.)
The Prior Art
Jasny teaches RNA which encodes a Lassa virus (LASV) glycoprotein (GP) for use in vaccine compositions, especially for treating or preventing a disorder or disease associated with LASV infection (entire document; see abstract.) Jasny teaches the glycoprotein of LASV forms a trimer of heterotrimers, wherein each comprises the receptor binding subunit GP1 and the transmembrane fusion-mediating subunit GP2, and a stable signal peptide (SSP)(¶[0225]). The glycoprotein precursor used in their disclosure (GPC) preferably comprises the full-length GPC that is a prefusion stabilized GPC (¶[0199]), as the full-length GPC is required to generate a GPC trimer (¶[0226]). The GPC comprises, in the N- to C- terminal direction, a SSP, GP1, cleavage site, GP2, transmembrane (TM) domain, and cytoplasmic domain (CD)(¶0227-0228]). In the Lassa virus LASV GPC, the trimerization of the GP is primarily mediated by the transmembrane domain (TM) of the GP2 subunit. The GP2 TM, along with the stable signal peptide (SSP), forms a central, helical transmembrane anchor that facilitates the trimerization of the GP1-GP2 heterodimers. Therefore, Jasny teaches every limitation of instant claims 1-5, 9, 20, and 27-28. Jasny teaches the RNA of the invention may be expressed in mammalian cells (¶[0059]; instant claim 30). Jasny teaches pharmaceutical vaccine compositions which comprise the trimeric-forming glycoprotein RNA (¶[0491]), wherein said compositions can be used to treat or prevent an infection with LASV through the administration of the composition in an effective amount to treat a subject in need (reference claim 49; ¶[0748]) or wherein said compositions can be used in methods of detection or diagnosis of LASV (¶[0760-0775]). Said RNA can be expressed to produce the peptides and proteins of LASV for use in vitro, in vivo, or ex vivo, especially for the treatment of LASV infection or related disorder and obtaining/detecting antibodies (¶[0774-0775]; instant claims 33-34, 36-43).
For at least these reasons, Jasny teaches the limitations of instant claims 1-5, 9, 20, 27-28, 30, 33-34, and 36-43 and anticipates the invention encompassed by said claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 9, 20, 27-28, 30, 33-34, and 36-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 12, 27, 32-33, 35-36, 38, 40-42, and 44-48 of copending Application No. 18/556,612 (reference application) in view of Eschli (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming recombinant arenavirus glycoproteins (GP) which comprise an ectodomain and a trimerization domain. Both claim that said ectodomain comprises a GP1/GP2 protein, wherein the trimerization domain is bound to the C-terminus of the GP2 protein. Both claim the presence of a protease cleavage site between the GP1/GP2 domains, both claim a signal domain bound to the N-terminus of the GP1 domain. Both claim the GP forms a trimer, both claim nucleic acids encoding said GP, cells which comprise nucleic acids encoding said GP or comprising said trimer, both claim vaccine compositions comprising either the trimer or the GP, and both claim methods of using the trimer or GP in methods of immunizing against arenavirus disease, methods of diagnosing the effectiveness of an arenavirus vaccine, and in methods of diagnosing arenavirus infection. While the reference claims provide the GP is derived from LCMV, such would be an obvious optimization for a skilled artisan, especially as instant dependent claim 38 provides that this is one of the potential arenaviruses that would be treated by the GP, and is further obvious as LCMV is a commonly studied arenavirus, and constructs comprising LCMV GP ectodomain-heterologous trimer domain are known in the art, as evidenced by Eschli (detailed supra). Therefore, the differences between the instant claims and the ‘612 claims are not patentably distinct, especially in light of the teachings of Eschli.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671