DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Priority
The instant application, filed 08/17/2023, is a 371 filing of PCT/EP2022/054128, filed 02/18/2022, and claims domestic benefit to US provisional application 02/19/2021 and foreign priority to EP21165577.4, filed 03/29/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 09/13/2023 is acknowledged. Claims 1-27 and 30-31 are amended. Claims 1-31 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/25/2023 (2), 08/29/2023, 07/24/2024, and 03/03/2025 are in compliance with the provisions of 37 CFR 1.97 except where noted below. Accordingly, the information disclosure statements have been considered by the examiner.
In the IDS filed 08/25/2023, FOR reference 50, WO 2013135615 A1, is not loaded to the file wrapper. Accordingly, the reference has been lined through and has not been considered. It is noted that it appears that WO 2013135612 A1 has been loaded in place of WO 2013135615 A1. Neither reference has been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
The incorporation by reference paragraph for the sequence listing in the specification amendment dated 08/17/2023 recites the size of the ASCII text file in kilobytes (KB) instead of the required bytes. See item 1) a) iii) or 1) b) iii) below.
The instant specification recites the following sequences without a corresponding SEQ ID NO:
GSGSG on page 13, line 10;
SAIG on page 13, line 24;
SAIG on page 14, line 6; and
SAIG on page 35, line 7;
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification Objection
The abstract is objected to for comprising phrases which can be implied, such as recitation of “The present invention provides” as well as legal phraseology, such as “said” proteins, nucleic acid molecules, and/or vectors.
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 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.
The disclosure contains the following embedded hyperlinks. Prefixes and non-top level domain browser-executable code is bolded for clarity:
Page 20, line 20: http://www.kazusa.or.jp/codon; and
Page 62, line 2: https://doi.org/10.1371/iournal.ppat.1007944
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-31 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.
Claims 1-8, and 11 are drawn to a stabilized pre-fusion RSV fusion (F) protein and recite amino acid positions that either comprise the recited amino acids (claims 1-8) or are deleted (claim 11). The amino acid positions recited in the claims are relative terms that depend on a sequence in which the positions are present. The claims; however, do not recite a sequence to which the recited positions could be referring. Additionally, the claims do not recite a numbering system that is used to identify the claimed positions. As such, the metes and bounds of the claims are indefinite.
Additionally, claim 1 recites that the stabilized pre-fusion RSV F protein comprises an amino acid sequence of “the F1 and F2 domain of an F protein of an RSV B strain, wherein the amino acid residue at position 101 is Q…”. This recitation suggests that the stabilized pre-fusion RSV B F protein must include the amino acid sequence of the F1 and F2 domain of an F protein of an RSV B strain; however, the claim then limits certain amino acids that are found within the F1 and F2 domains to being particular amino acids. It is unclear how the amino acid sequences can be both those from the F1 and F2 domain of an F protein while also including the amino acids recited in the positions recited, rendering the metes and bounds of the claims indefinite. This is particularly the case as the claims do not specify that the recited amino acids are substituted within the domains.
Appropriate correction is required.
Claims 9-10 and 12-31 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
Claim 1 recites a “stabilized” pre-fusion RSV F protein. “Stabilized” is a relative term which renders the claim indefinite. The term “stabilized” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the claim body does provide some structure for the RSV F protein, the claim encompasses a broad and variable scope such that it is not clear which structures of the protein would meet the limitation of the protein being stabilized.
The term “stabilized” is not explicitly defined in the disclosure. The plain meaning of the word stabilized is to make something stable, which implies that it is more stable than it previously was. The disclosure indicates that the claimed pre-fusion RSV B F proteins are stabilized by the presence of one or more stabilizing amino acids (either already present or introduced by mutations), i.e., do not readily change into post-fusion conformation upon processing of the proteins, such as e.g., purification, freeze-thaw cycles, and/or storage etc. (page 17).
As neither the claim nor the disclosure provide a requisite degree for ascertaining whether or not a pre-fusion RSV F protein is considered to be “stabilized”, the metes and bounds of the claim are indefinite.
Appropriate correction is required.
Claims 2-31 are rejected by virtue of their dependency on claim 1 as they do not resolve the ambiguity discussed above.
Claim 7 is drawn to the protein of claim 1 and recites the limitation “wherein the amino acid residue at position 172 is Q and the amino acid residue at position 172 is L. It is unclear how the amino acid at position 172 can be both Q and L at the same time, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
In the instant office action, the claim is interpreted as requiring that the amino acid at position 172 is Q and the amino acid at position 173 is L. This interpretation is supported by the instant specification, page 12.
Claim 9 recites the limitation “the furin cleavage sites” have been deleted. There is insufficient antecedent basis for this limitation in the claim. The claim depends on claim 1, which encompasses modified pre-fusion RSV F proteins and does not reference a parent protein, or any other protein, that necessarily includes furin cleavage sites that could be being referenced, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 26-29 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 inhibiting or reducing the spread of RSV or inhibiting or reducing the onset, development, or progression of one or more symptoms associated with RSV infection, does not reasonably provide enablement for preventing infection and/or replication of RSV. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Instant claims 26-29 are drawn to a method of preventing infection and/or replication of RSV in a subject comprising administering to the subject a vaccine against RSV comprising the protein of claim 1 and a pharmaceutically effective carrier.
Claim 27 further encompasses prevention of PT PCR-confirmed RSV-mediated lower respiratory tract disease (LRTD).
The breadth of the claims
The claims are broad in that they encompass the use of vaccines against RSV comprising the protein of claim 1 in the prevention of RSV and the prevention of replication of RSV in a subject.
The instant specification equates prevention with prophylaxis (page 31, lines 7-9).
The specification does not specifically define “preventing” or “prophylaxis”. In absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of RSV suggests that that the onset of RSV never occurs and the patient’s health is protected and preserved.
It is noted that the instant specification further states that prevention also encompasses inhibiting or reducing the spread of RSV or inhibiting or reducing the onset, development or progression of one or more of the symptoms associated with infection by RSV (page 32, lines 4-8). As the inhibition or reduction of these outcomes does not require that onset never occurs, such limitations would be enabled.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure detail the design of a soluble trimeric protein by the introduction of a C-terminal foldon and stabilizing point mutations in pre-fusion RSV F proteins. One or more of the point mutations P101Q, I152M, K226M, D486N, S215P, L203I, and/or D489Y were introduced and stability was studied compared to a non-stabilized protein, SEQ ID NO: 3. The examples further detail studies of the antigenicity of the preferred polypeptides comprising sequences of SEQ ID NOs: 14, 16, 17, and 18, and IC50 values were determined (Examples 1-6).
Example 7 studied preF B (RSV190420, SEQ ID NO: 17) in mice and cotton rats and the ability of the protein to induce antibodies capable of neutralizing RSV A and RSV B strains. In the study, mice were intramuscularly immunized with unadjuvanted RSV190420 protein on days 0 and 28. Cotton rats were also intramuscularly immunized with unadjuvanted RSV190420, or with RSV190420 adjuvanted with AdjuPhos at day 0 and day 28. Control groups received intramuscular immunization with formulation buffer (FB). Virus neutralizing antibody responses were measured at day 42 for mice or day 49 for cotton rats. Responses were measured using FFL assay for strains RSV A CL57 or RSV B1, using pRNT for strains RSV A2 or RSV B Wash, or using MN assay for clinical isolates RSV B 11-052009 and RSV B 17-058221. The example concludes that intramuscular immunization of mice or cotton rats with preF-B protein RSV190420 results in a dose-dependent induction of antibodies, which were capable of neutralizing different RSV A and RSV B strains, when assayed using various types of neutralizing assays. These results are reported as demonstrating that the preF-B protein is immunogenic in rodents and induces cross-neutralizing antibodies (pages 49-50, Example 7; Fig. 9).
Example 8 studied preF B protein RSV200125, SEQ ID NO: 18 in cotton rats for immunogenicity and protection against challenge with RSV A2 or RSV B wash (page 51). In the study, cotton rats were intramuscularly immunized with unadjuvanted RSV200125 at day 0 and day 28 and a control group received immunization with formulation buffer (FB). Animals were intranasally challenged at day 49 with RSV A2, or at day 50 with RSV B wash. Five days post challenge, lung and nose tissue was isolated and viral load was determined in plaque assays. Pre challenged sera was also isolated and assayed for virus neutralizing antibody responses. In the example, the majority of cotton rats immunized with any dose level of RSV200125 did not have detectable viral load after challenge with RSV A2 or B wash. In contrast, in the nose limited protection against RSV A2 was observed. RSV antibodies were detectable in the pre-challenge serum. The example concludes that the results demonstrate that preF-B protein is immunogenic and induces production against RSV A2 and RSV B wash challenge models in rats (page 51).
Example 9 studied adenoviral vector encoded single chain and processed RSV preF-B proteins and the ability of the proteins to induce cellular and humoral immune responses in mice. In the study, mice were immunized with viral particles of Ad26.RSV.preF-B single chain or processed variant and compared to a control group immunized with only buffer (FB). The example concludes that high RSV F directed cellular responses were induced after single immunization with both vectors (pages 51-52).
Example 10 studied immunogenicity and protective efficacy of RSV190414 (SEQ ID NO: 16), RSV190420 (SEQ ID NO: 17), and RSV200125 (SEQ ID NO: 18) in cotton rats using intranasal challenge with RSV B 17-058221. In the study, the immunized cotton rats did not have detectable viral load after challenge. Full protection in the nose was observed with RSV2000125, and several animals had breakthrough nose infection in the groups immunized with RSV190420 or RSV190414. Antibodies were detectable in the pre-challenge serum and were capable of neutralizing strains of RSV A and RSV B. The example concludes that different preF-B proteins are immunogenic and induce protection in RSV B 17-058221 challenge models (pages 52-53).
Example 11 studied immunogenicity and protective efficacy of Ad26 encoding processes preF-B (SEQ ID NO: 32) in cotton rats using intranasal challenge with RSV A2 or RSV B 17-058221. Cotton rats immunized with Ad26.RSV-B.preF did not have detectable viral load in the lung after challenge, with only a few cases of breakthrough lung infection in animals immunized with the lowest dose. Full protection in the nose from RSV B 17-058221 at certain vaccine doses were observed, but not for RSV A2 challenge. Antibodies were detectable in pre-challenge serum.
These studies demonstrate that the proteins used were capable of inducing immunogenic response and antibody production when used in immunization studies. The examples also demonstrate that the immunization provides at least some protection against viral challenge with RSV and, in some cases, a reduction of viral load in the lungs and nasal track of subjects challenged with RSV strains.
The disclosure, however, does not provide or demonstrate a method that could be used to identify a subject that would have predictably developed RSV in order to establish that the immunization with the claimed vaccine led to prevention of RSV infection.
Additionally, the studies provided do not necessarily identify that viral replication was prevented using the claimed vaccines. While the examples do demonstrate that the immunization produces an immune response and can lead to reductions in viral load, it is not evident from the examples that this reduction is a result of viral replication prevention as opposed to, for example, targeted killing of viral load by the antibodies produced. As such, an ordinarily skilled artisan would not be able to predictably identify that viral replication was prevented in a subject in order to establish that the limitations of the instant claims were met.
The state of the prior art / the level of predictability in the art
The prior art also does not provide a method that could be used to identify that a subject would have predictably developed RSV in order to establish that RSV onset was prevented or to establish that RSV viral replication was prevented in the subject.
Coultas, J.A., et al (2019) Respiratory syncytial virus (RSV): a scourge from infancy to old age Thorax (74); 986-993 teaches that RSV is the most common single cause of respiratory hospitalization in infants and is the second largest cause of lower respiratory infection mortality worldwide. In adults, RSV is an unrecognized cause of deterioration in health, particularly in frail elderly persons. Infection rates typically rise in late autumn and early winter causing bronchiolitis in infants, common colds in adults and insidious respiratory illness in the elderly. Virus detection methods, optimized for use in children, have low detection rate in adults, highlighting the need for better diagnostic tests (abstract). Coultas teaches that outbreaks of RSV disease occur each winter in temperate regions, normally beginning in autumn and early winter in Europe and North America (paragraph bridging columns, page 986).
Coultas teaches that age remains the biggest risk factor for bronchiolitis, with young children having small-diameter airways, impaired respiratory capacity, and low respiratory reserve. Risk is greatest at 1 month and decrease thereafter. Exposure to tobacco smoke and lack of breastfeeding have important additional effects through conclusions are limited by small sample size in these studies. Risk factors such as male sex, prematurity, congenital heart disease, and underlying pulmonary disease are also significant. Another strong risk factor is the presence of older siblings. Older siblings are a greater source of spreading infection than adults as they spend significant time in nurseries and schools where RSV can spread.
Coultas further teaches that, in elderly persons, the greatest risk factors are pulmonary disease (especially COPD) and functional disability as measured by activities of daily living. Interestingly, coronary artery disease and diabetes (both risk factors for severe influenza) are not associated with increased risk of RSV severe disease. RSV is also associated with significant morbidity and mortality in care home residents, with 12% of all adult RSV hospital admissions occurring in this group and with a mortality rate of 38% compared with 3% in patients admitted from the community (page 986, left column, risk factors). Coultas teaches that despite decades of intensive research, much remains to be discovered regarding the host response to RSV infection. The virus’s apparent immunomodulatory adaptations have so far evaded the efforts of vaccinologists and the attempts of clinal scientists to specifically ameliorate its clinical manifestations (page 991, right column, conclusion).
Shi, T., et al (2015) Risk factors for respiratory syncytial virus associated with acute lower respiratory infection in children under five years: systematic review and meta-analysis Journal of Global Health 5(2); 020416; 1-13 provides a systematic literature review across 4 databases and obtained unpublished studies from RSV global epidemiology network (RSV GEN) collaborators. Meta-analysis was performed to estimate odd ratios for individual risk factors for RSV associated ALRI in young children (abstract, background, methods). Shi teaches odds ratios for risk factors including prematurity, low birth weight, being male, siblings, maternal smoking, history of atopy, low parental education, passive smoking, daycare center attendance, indoor air pollution, no breastfeeding, and crowding (>7 persons) in the household (page 6, Table 4). Shi teaches various other potential risk factors including multiple births, HIV, malnutrition, altitude, previous illness, and lack of plumbed water in household (page 8).
The teachings of Coultas and Shi demonstrate a multitude of risk factors that potentially contribute to RSV infection and subsequent replication, including the region in which the subject lives, the time of year, age, gender, underlying diseases, and environmental factors such as exposure to smoke and the number and age of the people the subject comes into contact with and their exposure.
As there are numerous factors that contribute to the risk of developing RSV, it is apparent that there is not an established method that could be used to predictably identify that a subject would develop RSV infection and subsequent replication without the claimed vaccination in order to determine that the RSV infection, or replication thereof, was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed in detail above, there is no disclosed, or art recognized, method through which an ordinarily skilled artisan would be able to predictably determine that a subject would have predictably developed RSV and, subsequent replication thereof, in order to apply the claimed method as a preventative measure. Furthermore, as there is no known or art disclosed method that can be used to establish that RSV infection onset and replication thereof would have occurred, there is no way to know that the subject would have developed RSV infection/replication without the claimed method. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to find a method that could be used to determine that RSV infection onset was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Written Description
Claims 1-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a stabilized pre-fusion RSV fusion (F) protein comprising an F1 and F2 domain, comprising an amino acid sequence of the F1 and F2 domain of an F protein of an RSV B strain, wherein the amino acid residue at position 101 is Q, the amino acid at 152 is M, the amino acid residue at 215 is P, and the amino acid residue at position 486 is N.
Based on the current recitation, claim 1 is drawn to a genus of stabilized pre-fusion RSV F proteins that encompass any F1 and F2 domain amino acid sequences of an F protein from any RSV B strain, as long as the protein comprises at least 101Q, 152M, 215P, and 486N amino acids. Additionally, the claim uses “comprising” language with regards to the amino acid sequence. In the absence of a limiting definition by applicant for the term “comprising” the transitional phrase is interpreted per the definition in MPEP 2111.03 I, which states that comprising, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As such, in the broadest reasonable interpretation of the claim, the claim could include any other amino acid in any other position of the protein, so long as at least the four recited are present. Additionally, the claim recites “an” amino acid sequence in line 2. In the broadest reasonable interpretation of the claim, the use of “an” indicates that the claimed protein may comprise portions of the amino acid sequence of the F1 and F2 domains and still meet the instant claim requirements.
It is noted that this interpretation is supported by the instant specification, which indicates that the specific amino acids recited may already be present in the amino acid sequence of the RSV FB protein, or may be introduced by substitution (mutation) of a naturally occurring amino acid residue at that position into the specific amino acid residues according to the invention (page 10, lines 19-22).
Claim 1 further limits the pre-fusion RSV F proteins with the functional limitation of being “stabilized” pre-fusion RSV F proteins.
Claims 24-29 further recite functional limitations that the stabilized pre-fusion RSV F protein must be capable of performing, including functioning as a vaccine against RSV, functioning in a method for vaccinating a subject against RSV, and in a method preventing infection and/or replication of RSV in a subject. The claims also recite that prevention of infection and/or replication is characterized by the prevention or reduction of PT PCR-confirmed RSV mediated LRTD; absent or reduced viral load in the nasal track and/or lungs; and absent or reduced RSV clinical symptoms upon exposure to RSV.
Claims 2-8 further limit various other amino acids in the protein of claim 1. Specifically, claims 2-4 further limit the protein of claim 1 to having 489Y, 203I, or 226M amino acids, respectively; claim 5 further limits the protein of claim 1 to having amino acids 101Q, 152M, 203I, 215P, 226M, and 486N; claim 6 further limits the protein of claim 1 to having amino acids 101Q, 152M, 203I, 215P, 486N, and 489Y; claim 7 further limits the protein of claim 1 to having amino acids 172Q and 172L; and claim 8 further limits the protein to having amino acids 191R, 206M, and 209R.
Each of claims 2-8 remain drawn to a genus of stabilized pre-fusion RSV F proteins that are limited only by the requirement of having the recited amino acids present.
Claims 14 and 18 ultimately depend on claim 1 and recite that the protein comprises “an” amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 16, 17, 18, 29, 30, 32, and 34, “or fragments thereof”. Both the use of “an” in the claim as well as the recitation of “or fragments thereof” indicate that only portions of the recited sequences are required. As such, the claims remain drawn to a genus of pre-fusion RSV F proteins all of which are required to be stabilized.
The instant disclosure, however, does not provide a representative number of species of the claimed genus performing the recited functions nor does the disclosure identify a structure-function correlation which could be used to identify which species of the claimed genus would be capable of having the claimed functions.
The examples of the disclosure are as discussed in detail above. As discussed above, the examples detail the design of a soluble trimeric protein by the introduction of a c-terminal foldon and stabilizing point mutations. In example 1, several pre-fusion RSV F protein variants were produced. The soluble candidates were truncated at amino acid position 513 of RSV B F1 domain and fused with a four amino acid linker (SAIG) to a fibrin trimerization domain (foldon) of SEQ ID NO: 2. To stabilize the pre-fusion conformation of the proteins, several combinations of point mutations were introduced.
In the examples, point mutations were introduced in the parent, non-stabilized, preF B protein of SEQ ID NO: 3 and temperature stability of the proteins was studied. The polypeptides, and temperature stability thereof, are shown in Table 2 on page 44. Fig 2A also provides stability data for the polypeptides.
PNG
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1015
1368
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Greyscale
Based on the mutations disclosed in Table 2 and the stability data provided, RSV180916, RSV180917, RSV181180, RSV181181, RSV181182, RSV180913, RSV190414, RSV190420, and RSV200125 (indicated with a bracket on the left of the table above) represent species of stabilized RSV B F proteins that applicant was in possession of at the time of the effective filing date of the claimed invention. These RSV proteins are represented by SEQ ID NOs: 8, 9, 10, 11, 12, 14, 16, 17, and 18, respectively.
The examples further teach the stabilization of either a processed (SEQ ID NO: 25) or single-chain (SEQ ID NO: 26) full-length RSV-FB protein after transfection into expiHEK293F cells (page 48, example 6). A stabilized full length variant was produced containing 6 stabilizing amino acid substitutions including P101Q, I152M, L203I, S215P, D486N, and D489Y (SEQ ID NO: 29); as well as a stabilized single-chain variant with 5 substitutions including P101Q, I152M, L203I, S215P, and D486N (SEQ ID NO: 30). The example further discusses PR_stabilized (SEQ ID NO: 32) and SC-stabilized (SEQ ID NO: 34) processed and single-chain RSV-B F proteins comprising the stabilizing mutations of the invention (pages 48-49). Although it is noted that it is not readily apparent which combinations of substitutions were included in SEQ ID NO: 32 and 34.
These species, including 8, 9, 10, 11, 12, 14, 16, 17, 18, 29, 30, 32, and 34, represent the species of stabilized RSV B F proteins that applicant was in possession of at the time of the effective filing date of the claimed invention
These species, however, are not representative of the entire claimed genus of proteins which could comprise any parent sequence including wild-type or already modified RSV B F proteins so long as they comprise the F1 and F2 domain of any RSV B strain with the recited amino acids in the recited positions.
Furthermore, applicant does not provide a single species of a RSV FB protein in which the claimed specific amino acids are already present in the amino acid sequence of the RSV FB protein. Rather, in the examples, the amino acids are introduced by substitution (mutation) of a naturally occurring amino acid residue at the specific position in the disclosed non-stabilized parent sequence(s).
With regards to fragments, the disclosure indicates that fragments may result from either or both of amino-terminal and carboxy-terminal deletions. The fragment may be chosen to comprise an immunologically active fragment of the F protein, i.e., a part that will give rise to an immune response in a subject. The term “fragment”, as used, thus refers to a protein that has an amino-terminal and/or carboxy-terminal and/or internal deletion, but where the remaining amino acid sequences is identical to the corresponding positions in the sequence of an RSV FB protein, for example, the full-length sequence of an RSV FB protein (page 15, line 17 – page 16, line 4).
The disclosure does not provide any species of such fragments of SEQ ID NOs: 14, 16, 17, 18, 29, 30, 32, or 34, or any other protein, performing the claimed functions.
Additionally, the disclosure does not identify a structure-function correlation that could be used to identify which pre-fusion F proteins of an RSV B strain encompassed by the claimed genus would be capable of performing the functions as claimed. The disclosure also does not provide a structure-function correlation that could assist in identifying which fragments of the recited amino acid sequences in claims 14 and 18 would retain the required functions.
Rather, the teachings of the disclosure suggest that stabilization of the RSV F glycoprotein is not predictable and is based on protein folding and conformation. Specifically, the disclosure discusses the RSV F glycoprotein stating that it is an attractive vaccine antigen as it is the principal target of neutralizing antibodies in human sera. Most neutralizing antibodies in human sera are directed against the pre-fusion conformation, but, due to its instability, the pre-fusion conformation has a propensity to prematurely refold into the post-fusion conformation, both in solution and on the surface of the virions. Crystal structures have revealed a large conformational change between the pre-fusion and post-fusion states (page 2, line 19 – page 3, line 7). The disclosure further defines “stabilized pre-fusion protein” as referring to a protein that is stabilized in the pre-fusion conformation, i.e., that comprises at least one epitope that is specific to the pre-fusion conformation of the RSV F protein, e.g., as determined by specific binding of an antibody that is specific for the pre-fusion conformation to the proteins (page 11, lines 1-5).
The example provided also demonstrate a lack of predictability as each of the polypeptides in the examples are shown to have different stability and binding to RSV BF antibodies, which is suggested to be the result of differences in the proteins in the antibody footprints.
The disclosure also does not identify amino acids, and as such, epitopes, that must be maintained and does not provide a correlation between structure (amino acid sequence) and function (stability and the use as a vaccine).
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a structure-function correlation that would allow for the predictable identification of which pre-fusion RSV F proteins within the claimed genus would be stabilized and capable of performing the claimed functions.
For instance, US 2017/0182151 A1 (Che, Y., et al) 29 June 2017 teaches mutants of a wild-type RSV F protein comprising a F1 and F2 polypeptide wherein the amino acid mutation is selected from engineered disulfide bond mutations, cavity filling mutations, electrostatic mutations, and combinations thereof. US’151 also teaches that the mutant can be in the form of a trimer and that it can be RSV subtype B. US’151 teaches a multitude of mutations that can be made in the RSV F protein as shown in Tables 1-6. US’151 also exemplified various mutations and combinations of mutations in the RSV F protein and provides thermal and storage stability results in Example 4, Tables 7-8, where it is shown that stability varied significantly based on the specific mutation or specific combination of mutations that were introduced. US’151 also tested conformational integrity of the RSV F protein mutants using a panel of monoclonal antibodies in Example 5 (page 39), where it is disclosed that varying degrees of binding were observed across the mutants and with each of the antibodies tested. US’151 discloses that loss of binding indicated a lack of intact pre-fusion conformation (page 39, [0554]). US’151 also studied molecular weight and size distributions and discusses the impact of the nature of individual disulfide bonds and the overall compactness of the protein in the unfolded state and accessibility, demonstrating that intermolecular interactions between the amino acid sequences in the protein can change the conformation of the protein.
US’151 demonstrates that numerous point mutations and combinations thereof in RSV protein F F1 and F2 domains had been considered and studied in the art. The examples demonstrate that varying mutations result in varying stability and antibody binding, and therefore, immunogenicity.
US’151 further provides non-consensus amino acid residues among F protein sequences from RSV A and RSV B strains which include some overlap with the instantly claimed amino acids, for instance 101Q, 152M, and 226M, however, US’151 does not suggest that these mutations alone, or in combination with any other mutations could increase stability of the F protein.
Krarup, A., et al (2015) A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism Nature Communications 6(8143); 1-12 teaches that a RSV F protein that has both high expression levels and maintains a stable prefusion conformation would be a promising subunit vaccine candidate against RSV. Krarup sought to identify novel stabilizing mutations based on an understanding of the molecular basis of the prefusion instability and refolding pathway. The high degree of disorder observed previously in the HRA region, and especially in the apex of the protein, suggested that stabilization of this region might be important to maintain the prefusion conformation. Therefore, structure-based strategies to stabilize the apex by preventing the refolding of RR1 by arresting the fusion peptide and the hinging of a-helix 4 were studied. In addition, it was sought to lock the RR2 domain structure in place by reducing charge repulsion around the top of HRB, which is found at the bottom of the RSV F head (page 2, right column, paragraph 2).
Krarup studied mutations in positions including 67, 161, 173, 182, 214, and 215 with results shown in Fig. 3. The results also show the impact of using varying amino acids in these positions, particularly in position 67 and 215, in which it is demonstrated that some amino acids can increase stability while others do not. In Figure 4, Krarup also studied amino acid substitution combinations to test potential additive effects on stability. A shown, results demonstrate varying stability with mutations in the single chain and processed formats.
US’151 and Krarup do not provide representative species of the instantly claimed stabilized pre-fusion F protein nor does US’151 and Krarup provide a structure-function correlation that could be used to predictably identify which species of the claimed genus would perform the claimed functions. Rather, the teachings of US’151 and Krarup suggests that each mutation could impact stability, conformation, and antibody binding and; therefore the immunogenicity of the peptide.
Neither the instant disclosure, nor the prior art, provide a representative number of species of the claimed genus performing the recited functions. The disclosure and prior art also do not demonstrate or teach a structure-function relationship that would allow for the predictable identification of which species within the claimed genus would be capable of performing the claimed functions. As such, the instant claims were found not to meet the written description requirements of 35 USC 112(a).
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.
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Claims 1, 4, 10-13, 16-17, 19, 22-23, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,331,077 B2 in view of Krarup, A., et al (2015) A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism Nature Communications 6(8143); 1-12.
US’077 claims a recombinant pre-fusion RSV F protein comprising stabilizing amino acid mutations on positions 101, 152, and 486, wherein the amino acid on position 101 is Q, 152 is M, and 486 is N, and wherein the stabilizing amino acid mutations on the indicated positions increase the stability of the protein in the pre-fusion conformation, and wherein the amino acid positions of the F protein are numbered with reference to the numbering of the F protein of SEQ ID NO: 13 for RSV A or 14 for RSV B. The claims further recite mutations of 79M, 354L, and 226M and claims proteins with four, five, six, or more mutations. US’077 further claims that the protein is trimeric. US’077 claims that the protein has a truncated F1 domain and a heterologous trimerization domain linked to the truncation domain, where the heterologous trimerization domain comprises the amino acid sequence of SEQ ID NO: 15, which is identical to instant SEQ ID NO: 2, and is claimed US’077 as being linked at amino acid residue 513 of the RSV F protein, indicating removal of amino acids in F1 starting at 514. US’077 further claims a nucleic acid molecule encoding the pre-fusion RSV F protein according to claim 1, a vector comprising the nucleic acid molecule, and a composition comprising the recombinant protein and a pharmaceutically acceptable carrier. US’077 claims a method of inducing an immune response against RSV F protein in a subject comprising administering the composition as well as methods of preventing and/or treating RSV infection.
US’077 differs from the instantly claimed invention in that in that the instantly claimed invention further includes a mutation of 215P.
The teachings of Krarup are as discussed above.
Krarup teaches that S215P provided a strong stabilizing effect (page 3, left column, paragraph 1; Fig. 3, page 4). Krarup also studied the S215P mutation in various combinations including with a 486N mutation and demonstrates strong stability (page 5, Fig. 4).
It would have been prima facie obvious to one of ordinary skill in the art to add a 215P mutation to the claims of US’077 based on the teachings of Krarup. An ordinarily skilled artisan would have been motivated to include this mutation as Krarup demonstrates that the mutation has a significant stabilizing effect on the F protein of RSV both alone and in combination with other mutations, including 486N, which is a mutation that is included in US’077. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’077 and Krarup are drawn to mutations in the RSV protein F domain and their use in stabilizing the protein for use as a vaccine.
Claims 9, 15, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,331,077 B2 in view of Krarup, A., et al (2015) A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism Nature Communications 6(8143); 1-12 as discussed above regarding claims 1 and 16, and in further view of WO 2015/177312 A1 (Carfi, A., et al) 26 Nov. 2015.
The claims of US’077 modified by Krarup would lead an ordinarily skilled artisan to the stabilized RSV F protein of instant claims 1 and 16 as discussed in detail above.
The instant claims differ from the combination of US’077 and Krarup in that US’077 and Krarup do not disclose that the furin cleavage sites have been deleted, that the protein does not comprise a signal peptide, p27 peptide, or tag sequence, or an isolated host cell comprising a nucleic acid encoding the protein.
WO’312 teaches complexes that contain RSVF ectodomain polypeptides in prefusion form (abstract). WO’312 teaches that a potential approach to producing a vaccine is a subunit vaccine based on purified RSVF protein. However, for this approach it is desirable to have the purified RSVF protein in a single format conformation that is stable over time, consistent between vaccine lots, and conveniently purified (page 1, line 30 – page 2, line 12). WO’132 further teaches that, in some embodiments, the RSVF is a single-chain molecule, where the F1 and F2 domains lack an intervening furin cleavage site (page 13, lines 16-20). WO’312 further teaches that the ectodomain can be an F0 form with or without the signal peptide and all or a portion of the p27 domain may be absent (page 18, lines 14-21). WO’312 further teaches the omission of the tag sequence (page 32, lines 29-34). WO’312 further teaches that the RSV ectodomain polypeptides are prepared by expression in a recombinant host system by expression of recombinant constructs that encode the ectodomains. Preferable recombinant host cells are mammalian culture cells that can be readily transfected and/or in which stable lines can be generated for expression of the peptides (page 36, lines 16-24).
It would have been prima facie obvious to one of ordinary skill in the art to modify the pre-fusion RSV F protein disclosed by the combination of US’077 and Krarup with the teachings of WO’312 by deleting the furin cleavage sites, omitting the signal, p27, or tag sequences, and using an isolated host cell comprising a nucleic acid encoding the protein to express the protein. It would have been obvious to make these modifications, and one of ordinary skill in the art would have had a reasonable expectation of success as WO’312 also teaches RSV F proteins for vaccination against RSV and teaches these alternatives as formats that can be used in such vaccine development.
Claims 20-21, 23, and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,331,077 B2 in view of Krarup, A., et al (2015) A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism Nature Communications 6(8143); 1-12 as discussed above regarding claims 1 and 16, and in further view of US 2019/0125854 A1 (Langedijk, J.P.M. and J.M. Verhagen) 2 May 2019.
The claims of US’077 modified by Krarup would lead an ordinarily skilled artisan to the stabilized RSV F protein of instant claims 1 and 16 as discussed in detail above.
The instant claims differ from the combination of US’077 and Krarup in that US’077 and Krarup do not disclose that the vector is a replication incompetent Ad26 adenoviral vector having a deletion of the E1/E3 region or a host cell comprising the vector.
US’854 teaches nucleic acid molecules encoding a pre-fusion RSV F protein or immunologically active parts thereof and use of said nucleic acids alone or in vectors as a vaccine against RSV (abstract). US’854 teaches that RSV vaccines comprising human adenovirus comprising nucleic acids encoding RSV F protein have previously been described. It has been shown that recombinant adenoviruses of serotype 26 or 35 that comprise a nucleic acid encoding an RSV F protein are very effective vaccines against RSV in well-established cotton rat models and have improved efficacy compared to Ad5 encoding RSV F protein (page 3, [0032]). US’854 teaches that, in some embodiments, the adenoviral vector is deficient in at least one essential gene function of the E1 region that is required for replication and deficient in at least part of the non-essential E3 region (page 4, [0046] and [0049]).
US’854 further teaches a producer cell, sometimes referred to as a host cell, that can be used to propagate a desired adenovirus (page 4, [0050]).
US’854 further teaches compositions that comprise a nucleic acid and/or vector for use in reducing infection and/or replication of RSV in a subject. In certain preferred embodiments, the compositions are used as a vaccine against RSV (page 5, [0060])
It would have been prima facie obvious to one of ordinary skill in the art to modify the pre-fusion RSV F protein disclosed by the combination of US’077 and Krarup with the teachings of US’854 by using a human Ad26 vector with an E1/E3 deletion rendering the vector replication incompetent as well as host cells comprising the vectors. It would have been obvious to make these modifications, and one of ordinary skill in the art would have had a reasonable expectation of success as US’854 also teaches RSV F proteins for vaccination against RSV and teaches these vectors as ones that can be used in such vaccine development.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693