DETAILED ACTION
Disposition of Claims
Claims 1 and 3-10 are pending.
Examiner’s Note
The examiner of your application in the Patent and Trademark Office has been reassigned. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Rachel Gill, Art Unit 1671.
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250073332A1, Published 03/06/2025.
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 10/04/2023, 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
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Election/Restrictions
Applicant’s election of the species “Large S antigen”, “SEQ ID NOs: 13 and 15” in the reply filed on 04/24/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In light of the application changing examiners, this restriction/election requirement between species set forth on 03/12/2026 is hereby withdrawn. All non-elected species are hereby rejoined and will be examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/04/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 implied phraseology (e.g. “The invention discloses…”. 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).
Claim Objections
Claims 3 and 4 are objected to because of the following informalities: claim 1 recites “at least one Large S hepatitis B virus antigen”, and claims 3 and 4 refer to “the large S antigen”. Since the wording of claim 1 allows for 1 or more “Large S antigens/proteins” to be present, it is suggested that claims 3 and 4 be amended along the lines of the following to place them in better form: “…wherein the at least one large S hepatitis B virus antigen comprises an amino acid sequence set forth as SEQ ID NO: 13.” and “…wherein the sequence encoding at least one large S hepatitis B virus antigen is the sequence set forth as SEQ ID NO: 15.” Appropriate correction is required.
Claims 5-6 and 9 are objected to because of the following informalities: “the lentiviral vector as defined in claim 1” may be confusing in view of the fact that claim 1 is now directed to a method, not a viral vector per se. While claim 1 does recite a lentiviral vector, it would place the claims in better form if the claims were amended to read upon the specific lentiviral vector envisaged (e.g. for claim 9, “…comprising: a) a lentiviral vector, wherein said vector comprises a nucleotide sequence encoding at least one Large S hepatitis B virus antigen; and b) a pharmaceutically acceptable carrier.”). 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.
Claim 1 and dependent claims 3-10 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 “method of treating hepatitis B”. However, from the wording of the claim and further dependent claims, it is unclear if the method as claimed (e.g. “treating hepatitis B”) requires treatment of hepatitis B virus (HBV) infection itself, treatment of chronic hepatitis B hepatitis, reduction of viral load, HBsAg clearance, prevention of infection, treatment of symptoms, treatment of liver disease caused by HBV, or some other clinical endpoint.
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 3-10 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claim 7 and dependent claim 8 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 7 is drawn to the method according to claim 1, for the treatment and/or prevention of hepatitis B virus infection in a subject in need thereof, or for the treatment and/or prevention of diseases caused by hepatitis B virus infection. However, claim 1 already recites that said method is to “treat Hepatitis B”, and in light of the 35 USC 112b rejection supra, it is unclear if claim 7 is further limiting this preamble statement, or if claim 7 is attempting to broaden the scope of claim 1 to include “prevention”, or merely restate the intended use. It is unclear what additional step, condition, subject population, disease state, or therapeutic endpoint is required by this limitation beyond the treatment method already recited in claim 1. The introduction of “prevention” and “disease caused by hepatitis B virus infection” causes confusion as the claim does not clearly define whether the claimed method requires treatment, prevention, treatment of infection, prevention of infection, treatment of a disease caused by infection, or prevention of such a disease. Finally, the antecedence of “subject” in claims 7 and 8 does not clearly refer back to “individual” in claim 1. For at least these reasons, the claim does not clearly set forth the scope of the subject matter.
One suggestion is to amend the claim to recite the endpoint desired for each of these limitations: “…wherein the administering treats hepatitis B virus infection”, or “wherein the administering prevents hepatitis B virus infection” or “wherein the administering treats or prevents diseases caused by hepatitis B virus infection, wherein the diseases are [specific diseases]”.
For at least these reasons, claim 7 is rejected on the grounds of being indefinite. Claim 8 is rejected for depending on claim 7, but for not clarifying the metes and bounds of claim 7.
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 method of treating hepatitis B, comprising administering to an individual in need thereof a lentiviral vector comprising a nucleotide sequence encoding at least one Large S hepatitis B virus antigen.
Further limitations on the method according to claim 1 are wherein the at least one large S hepatitis B virus antigen comprises an amino acid sequence set forth as SEQ ID NO: 13 (claim 3); and wherein the sequence encoding at least one large S hepatitis B virus antigen is the sequence set forth as SEQ ID NO: 15 (claim 4); wherein the administering treats hepatitis B virus infection, or wherein the administering treats disease associated with hepatitis B virus infection (claim 7), wherein the individual is a mammal (claim 8).
Claim 5 is drawn to a method for preparing lentiviral particles for treating hepatitis B, characterized in that the method comprises:
a) co-transfecting host cells with:
i) a lentiviral vector, wherein said vector comprises a nucleotide sequence encoding at least one Large S hepatitis B virus antigen;
ii) a packaging vector expressing Gag, Rev and/or Pol protein; and
iii) an envelope vector expressing an envelope protein, or
transfecting a lentiviral vector, wherein said vector comprises a nucleotide sequence encoding at least one Large S hepatitis B virus antigen; into a host cell capable of expressing an envelope protein and one or more of Gag, Rev, and Pol proteins;
b) culturing the transfected host cell to package the lentiviral vector into lentiviral vector particles; and
c) harvesting the lentiviral vector particles produced in step b).
Claim 6 is drawn to a preparation of lentiviral particles for the treatment of hepatitis B, wherein the lentiviral particles comprise a lentiviral vector, wherein said vector comprises a nucleotide sequence encoding at least one Large S hepatitis B virus antigen.
Claim 9 is drawn to a pharmaceutical composition for the treatment and/or prevention of hepatitis B virus infection or for the treatment and/or prevention of a disease caused by hepatitis B virus infection in a subject in need thereof, the pharmaceutical composition comprising:
a) a lentiviral vector, wherein said vector comprises a nucleotide sequence encoding at least one Large S hepatitis B virus antigen, and
b) a pharmaceutically acceptable carrier.
Further limitations on the pharmaceutical composition according to claim 9 is wherein the subject is a mammal (claim 10).
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 and 3-10 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 and 3-10 are rejected as lacking adequate descriptive support for any composition comprising any lentiviral vector comprising any hepatitis B virus (HBV) large S antigen and any method of making or using said vector which results in the claimed function of any therapeutic treatment of hepatitis B.
In support of the claimed genus (any HBV large S antigen), the application discloses one example in which two HBV Large S amino acid sequences were presented, one for genotype B (SEQ ID NO:10) and one for genotype C (SEQ ID NO: 13), along with a coding sequence for each respective protein. There are ten known HBV genotypes in the art, with genotypes A-D being the most common and genotypes being localized to regions (e.g. genotype E to Africa, genotype F to South America), and there are over 40 subgenotypes, with different genotypes correlating to higher risk of cirrhosis and hepatocellular carcinoma (e.g. genotype C is often associated with more severe disease than genotype B). The working example notes that only plasmids containing HBV type C human codon-optimized sequences, namely preS1, large S, and Core antigens, were generated in an undisclosed lentiviral vector plasmid system that generated pseudotyped lentiviral particles which incorporated the G protein from either Indiana or New Jersey serotype of vesicular stomatitis virus (VSV)(¶[0072-0079]). Mice were injected with AAV8-1.3HBV to establish a persistent HBV infection model from HBV genotype D (¶[0080-0081]), and the mice were inoculated with JW27 (type C Core antigen; SEQ ID NOs: 1, 3), JW28 (type C preS1; SEQ ID NOs: 7, 9), JW29 (type C large S; SEQ ID NOs: 13, 15), or JW30 (GFP control virus) lentiviruses intramuscularly (¶[0081]). The prime/boost lentivirus vaccinations occurred with a heterologous pseudotyped virus, as the priming virus comprised Indiana VSV G while the boosting viruses comprises VSV New Jersey G (Fig. 2; Table 2; ¶[0098]). The immune response which elicited the strongest response against different HBV genotypes (only genotypes B and C appear to have been tested) was that in response to the Large S vaccine (JW29; Fig. 5, ¶[0106-0107]). No derivatives, variants, or mutants of HBV large S were generated, tested, or disclosed, namely no other Large S protein from any other genotype was incorporated into any lentiviral vector and tested for its ability to treat hepatitis B in any way. The working data are limited to these specific noted constructs in this limited animal model. The disclosure fails to provide a representative number of large S antigen species across the full scope of the claimed genus, nor does it identify a common structural feature common amongst genotypes that is sufficient to show possession of all Large S antigen sequences that would be encoded by any lentiviral vector, especially for use in any treatment of any hepatitis B infection or disease. Thus, the application fails to provide a sufficient number of examples of species within the claimed genus.
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 Large S HBV antigen can be used to treat any form of hepatitis B. Prevention or treatment of HBV infection by a large S HBV antigen is very genotype and variant dependent. Washizaki et. al. (Washizaki A, et. al. Nat Commun. 2022 Sep 5;13(1):5207.) reported that Large-HBSAg vaccine-induced antibodies could neutralize certain vaccine escape mutations, but neutralization differed among HBV genotypes, and antibodies induced by a single HB vaccine did not neutralize all HBV genotypes at the same level. This variation amongst cross-neutralization was noted in the art with other studies (Kato M, et. al. J Gastroenterol. 2017 Sep;52(9):1051-1063. Epub 2017 Feb 14.) Washizaki and others further cautioned that neutralization of genotypes other than the vaccinated genotype may not be feasible if antibody titers are insufficient or decline over time (Inoue T, et. al. Vaccines (Basel). 2020 Aug 16;8(3):456.) Therefore, the art has recognized that a single example within the expansive genus of “Large S antigen” for HBV is not representative of the entire genus, especially with the therapeutic response said antigen may elicit in a subject.
Lentiviral vectors pseudotyped with VSV-G were conventional gene therapy vehicles, and the art recognized that VSV-G pseudotyping provided broad host range/tropism and favorable particle stability. However, VSV-G pseudotyping primarily addresses vector entry/production properties; it does not make therapeutic efficacy predictable. Vector function may still vary with the lentiviral backbone, safety configuration, promoter, pseudotype, target cell type, dose, route, and encoded antigen. Therefore, although a skilled artisan may have been able to make VSV-G pseudotyped lentiviral particles, the state of the art did not establish that the full claimed genus of any lentiviral vector encoding any Large S HBV antigens would reliably treat hepatitis B or treat or prevent any HBV infection. See e.g. Cronin J, et. al. Curr Gene Ther. 2005 Aug;5(4):387-98. Erratum in: Curr Gene Ther. 2005 Oct;5(5):531.; Dautzenberg IJC, et. al. Gene Ther. 2021 Feb;28(1-2):89-104. Epub 2020 Sep 24.
Thus, in view of the above, there would have been significant uncertainty as to which Large S HBV antigen would be engineered within any lentiviral vector and be able confer the claimed therapeutic effect of treatment of any type of hepatitis B. In view of this uncertainty and the lack of sufficient examples of the claimed genus, the claims are rejected for lack of adequate written description support.
Claims 1 and 3-10 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 VSV-pseudotyped lentiviral vectors delivering a human codon-optimized nucleic acid which encodes SEQ ID NO: 13 (Large S HBV antigen from genotype C) for eliciting an immune response against HBV, does not reasonably provide enablement for any lentivirus vector delivering any Large S HBV antigen for prevention or treatment of any HBV infection or disease. 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 method of treating hepatitis B, comprising administering to an individual in need thereof a lentiviral vector comprising a nucleotide sequence encoding at least one Large S hepatitis B virus antigen. Further claims are drawn to a method of preparing the lentiviral vector comprising a nucleotide sequence encoding at least one Large S hepatitis B virus antigen and pharmaceutical compositions comprising said lentiviral vector, especially for use in the treatment and/or prevention of any hepatitis B virus (HBV) infection or any disease in any subject in need thereof. The claims broadly encompass administration of any lentiviral vector comprising any nucleotide sequence encoding any Large S HBV antigen, without limitation to a particular HBV genotype, Large S sequence, codon-optimized sequence, vector backbone, pseudotype, promoter, integration-defective configuration, dose, route of administration, treatment endpoint, prophylactic endpoint, disease stage, or patient population.
“Hepatitis B virus” is any member of the species Orthohepadnavirus hominoidei that is a partially double-stranded DNA virus which has at least ten known HBV genotypes (A-J) and over 40 subgenotypes, with different genotypes correlating to higher risk of cirrhosis and hepatocellular carcinoma (e.g. genotype C is often associated with more severe disease than genotype B). The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes present on its envelope proteins, and further divided into subtypes, which mainly differ depending on geographic location. Genotypes and serotypes do not directly map one-to-one with one another, as serotypes are based upon serological reactivity of the HBsAg.
“Hepatitis B” is a contagious liver infection caused by the Hepatitis B virus (HBV), transmitted through contact with infected blood, semen, or body fluids. It can cause acute, short-term illness or chronic, long-term infection leading to cirrhosis, liver failure, or cancer.
“Large S antigen” is also known as the L-protein and is the largest of the three specific forms of the hepatitis B virus surface antigen (HBsAg). The Large S antigen comprises the entire S-region plus both pre-S1 and pre-S2 domains, and is essential for viral entry into liver cells.
“Prevention of HBV infection in a subject/individual" is interpreted to encompass the complete blockade of any individual cell within the subject from HBV infection.
State of the prior art/Predictability of the art. With respect to the art regarding lentiviral vectors, at the time of the invention, lentiviral vectors were a well-developed gene-delivery platform, and pseudotyping lentiviral particles with heterologous viral envelope glycoproteins was known to alter or expand vector tropism. In particular, vesicular stomatitis virus (VSV) G glycoprotein (VSV-G) was commonly used for lentiviral vector pseudotyping because VSV-G-pseudotyped particles exhibit broad tropism, can transduce many dividing and non-dividing mammalian cell types, and have favorable physical stability for vector production and concentration. However, VSV-G pseudotyping was also understood to provide broad, relatively non-targeted tropism rather than disease-specific or antigen-specific delivery, and vector performance could still depend on variables such as the lentiviral backbone, generation/safety configuration, envelope pseudotype, protomer, target cell type, vector dose, and route of administration. Therefore, while the general production of VSV-G pseudotyped lentiviral particles may have been within the skill in the art, that conventional knowledge would not by itself establish that any lentiviral vector encoding any HBV large S antigen would predictably treat hepatitis B of any etiology or prevent HBV infection across the full scope of the claims. See e.g. Cronin J, et. al. Curr Gene Ther. 2005 Aug;5(4):387-98. Erratum in: Curr Gene Ther. 2005 Oct;5(5):531.; Dautzenberg IJC, et. al. Gene Ther. 2021 Feb;28(1-2):89-104. Epub 2020 Sep 24.
Although lentiviral vector production was known, the therapeutic performance of a lentiviral vector is highly dependent upon vector design. Milone et. al. (Milone MC, et. al. Leukemia. 2018 Jul;32(7):1529-1541. Epub 2018 Mar 22.) explains that the lentiviral systems vary by generation, pseudotype, packaging design, SIN (self-inactivating to prevent recombination) configuration of the vector, and types of internal promoters used, and Milone teaches that the promoter activity of the vector may vary substantially in primary cells. Accordingly, routine ability to make a lentiviral particle does not establish enablement of the full scope of treatment or prevention of Hepatitis B or HBV infection using any lentiviral vector encoding any Large S antigen.
With respect to the state of the art regarding HBV therapeutic and/or prophylactic vaccination, a clinically available vaccine against HBV has been available for over 40 years. Current vaccines are a series of injections that are first administered in infancy, with booster vaccinations recommended only post-vaccination titers show waning immunity. It has a 90-95% effective rate, but is a prophylactic, not therapeutic, vaccine. Common commercially available HBV vaccines include Engerix-B (HBsAg+AlOH3 adjuvant), HEPISLAV-B (HBsAg+ CpG1018 adjuvant), and Recombivax HB (HBsAg+aluminum hydroxyphosphate sulfate adjuvant).
However, while lentiviral vector systems and HBV vaccines were known in the art at the time of filing, the combination of the two was not routine or predictable. Post-filing art has shown that HBV therapeutic vaccination through lentiviral vectors was still experimental and unpredictable. Zhang et. al. (Zhang Y, et. al. J Hepatol. 2024 Jan;80(1):31-40. Epub 2023 Oct 11.) reported that immunotherapy for chronic HBV infection had not yet demonstrated sufficient efficacy, and although a non-integrative lentiviral-vectored Large HBsAg vaccine reduced HBsAg and viral load in a HBV-persistent mouse model, the limited human data consisted of only two inactive HBsAg carriers with modest HBsAg reductions rather than demonstrated treatment or prevention of HBV disease or infection. Thus, even current art shows that it was not clear that lentiviral vectors encoding any Large S HBV antigen would predictably treat hepatitis B or prevent HBV infection in subjects generally.
Furthermore, while HBV prophylactic vaccines were known in the art, treatment for established HBV infections has been challenging. Chronic HBV treatment involves an unpredictable immunological context. Hoogeveen et. al. (Hoogeveen RC, et. al. Front Immunol. 2020 Mar 4;11:401.) explains that most chronic HBV patients require long-term nucleos(t)ide analogue therapy because existing therapy suppresses replication but is not curative, and functional cure is rarely achieved. The same review states that whether therapeutic can sufficiently restore antiviral T cell immunity to induce long-term HBV control remains an open question. This supports that the claimed therapeutic result would not have been predictable across the full scope of Large S antigen sequences, vector configurations, doses, routes, and patient populations.
Clinical experience with HBV therapeutic vaccines further demonstrates unpredictability. For example, Lok et. al. (Lok AS, et. al. J Hepatol. 2016 Sep;65(3):509-16. Epub 2016 May 19.) reported that GS-4774, a therapeutic vaccine for chronic HBV, was well tolerated but did not provide significant reductions in serum HBsAg in virally suppressed chronic hepatitis B patients. This supports that induction of HBV-specific immunity by a vaccine platform does not predictably translate into treatment of chronic HBV.
Prevention of HBV infection by a Large S antigen vaccine is also genotype and variant dependent. Washizaki et. al. (Washizaki A, et. al. Nat Commun. 2022 Sep 5;13(1):5207.) reported that Large HBsAg vaccine-induced antibodies could neutralize certain vaccine-escape mutations, but neutralization differed among HBV genotypes, and antibodies induced by a single HBV vaccine did not neutralize all HBV genotypes at the same level. The reference further cautioned that neutralization of genotypes other than the vaccinated genotype may not be feasible if antibody titers are insufficient or decline over time. Therefore, the art does not support predictable prevention of HBV infection across all Large S antigens, HBV genotypes, variants, routes, subjects, or dosing regimens.
Working examples. The working example disclosed in the specification was detailed supra in the written description rejection. Briefly, the working example only provided data for specific lentiviral constructs, the sequences for which were not disclosed, only the HBV antigen sequences were provided for in the specification. Those constructs included JW29, which comprised a human-codon optimized sequence encoding for a genotype C Large S sequence, and determined the efficacy of inoculation with said lentiviral construct in an AAV-HBV mouse model. The specification did not provide detail with how to make the specific lentiviral construct used beyond the HBV antigen delivered; no other Large S HBV antigens (e.g. other sequences, other genotypes, other serotypes) were tested for their ability to treat or prevent HBV infection or hepatitis B. No other HBV variants, strains, or pseudotypes were tested for their ability to be “treated” or “prevented” by any of these constructs. No other different lentiviral backgrounds or pseudotypes (aside from the VSV G Indiana and New Jersey pseudotypes) were tested, no other expression cassettes, patient populations, or different forms/stages of HBV infection were tested against any of the claimed lentiviral vectors.
Guidance in the specification. The specification provides guidance towards the delivery of JW29 to a subject in need thereof. The breadth of the claims, however, is substantially broader than the working examples or the guidance provided for in the specification. Although lentiviral packaging techniques may have been known in the art at the time of filing, the disclosure does not establish what type of lentiviral packaging system to use, or that all or substantially all lentiviral vectors encoding all Large S HBV antigens within the scope of the claim would treat hepatitis B or prevent HBV infection. JW29 only comprised a human-codon optimized sequence for encoding a single example of a genotype C Large S antigen (SEQ ID NO: 15) and did not provide guidance towards any other mutants, variants, genotypes, or serotypes that would result in the claimed therapeutic genus.
Amount of experimentation necessary. Additional research is required in order to determine how effective any lentiviral vector encoding any Large S antigen of HBV would be in the treatment or prevention of any hepatitis B or HBV infection in any patient population.
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, undue experimentation would be required to determine which Large S antigen sequences, nucleotide sequences, lentivirus vector design, doses, routes of administration, subject/patient populations, and treatment/prevention endpoints would successfully treat hepatitis B, prevent HBV infection, or prevent diseases caused by HBV infection across the full scope of the claims.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make the claimed compositions and 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 and 5-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chai et. al. (US20110257080A1, Pub. 10/20/2011; hereafter “Chai”.)
The Prior Art
Chai teaches lentiviral vectors that can be used as therapeutic and prophylactic vaccines for treatment of HBV infection or hepatitis B disease (entire document; see abstract, ¶[0024][0152][0170][0195-0196]), wherein said vectors comprise an envelope surface protein of hepatitis B virus, namely the L protein (abstract; ¶[0008][0148][0218-0223]). Chai teaches plasmids which encode the L protein (¶[0148][0156]), and teaches singular vectors which encode the lentiviral and HBV proteins (¶[0158]). Chai teaches administration of the compositions to elicit a protective immune response against HBV infection (¶[0212]). Chai therefore teaches lentiviral vectors which comprise nucleic acid encoding HBV L antigen, and methods of delivering said vectors to prophylactically or therapeutically inhibit HBV infection or hepatitis B, and teaches the limitations of instant claims 1 and 6-7.
Chai teaches methods for preparation of the lentiviral particles (¶[0149-0151]), wherein a host cell is transfected with two or more vectors carrying the packaging functions, the transfected cells are cultured, allowing the cells to produce the lentiviral vector particles, wherein said particles are harvested directly from the cell culture medium (¶[0151][0179]; instant claim 5). Chai teaches the subject treated with the particles is a mammal (¶[0153][0195]; instant claim 8, 10). Chai teaches the vaccine comprising the lentiviral vectors may be a pharmaceutical composition, which comprises a pharmaceutically-acceptable carrier (¶[0141]; instant claim 9).
For at least these reasons, Chai teaches the limitations of instant claims 1 and 5-10, and anticipates the invention encompassed by said claims.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NOs: 13 and 15 appear to be free of the prior art of record.
Conclusion
No claims are allowed. SEQ ID NOs: 13 and 15 appear to be free of the prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Markusic DM, et. al. Hum Gene Ther. 2007 Jul;18(7):673-9. Teaches lentivirus expressing a portion of the Large antigen from HBV.
US20190160166A1. Teaches Lentiviral vectors delivering HBV antigens.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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