DETAILED ACTION
Disposition of Claims
Claims 1-17 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240197854A1, Published 06/20/2024.
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 07/28/2023, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/28/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification - Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains reference to at least one drawing executed in color (see e.g. ¶[0035-0036] for figures 1-2 legends). Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings and specification are objected to because:
Figs. 1-2 have reference to color within the drawings.
Figs. 7 and 21 have a large number of sequences, and the figure legend is not clear. Each individual sequence in the figures should comprise somewhere in the figure the SEQ ID NO: that is associated with each sequence for clarity of the record.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: at ¶[0006], it is noted that the mutations are according to “HXB2 numbering”. Said sequence is Ido et. al. Envelope polyprotein [Human immunodeficiency virus 1]. GenBank: AAB50262.1. 10/21/2002. The amino acid mutations within the specification do not appear to correspond to the amino acids at these positions, so it is unclear what “base” sequence was used for the Env protein.
1 MRVKEKYQHL WRWGWRWGTM LLGMLMICSA TEKLWVTVYY GVPVWKEATT TLFCASDAKA 61 YDTEVHNVWA THACVPTDPN PQEVVLVNVT ENFNMWKNDM VEQMHEDIIS LWDQSLKPCV 121 KLTPLCVSLK CTDLKNDTNT NSSSGRMIME KGEIKNCSFN ISTSIRGKVQ KEYAFFYKLD 181 IIPIDNDTTS YKLTSCNTSV ITQACPKVSF EPIPIHYCAP AGFAILKCNN KTFNGTGPCT 241 NVSTVQCTHG IRPVVSTQLL LNGSLAEEEV VIRSVNFTDN AKTIIVQLNT SVEINCTRPN 301 NNTRKRIRIQ RGPGRAFVTI GKIGNMRQAH CNISRAKWNN TLKQIASKLR EQFGNNKTII 361 FKQSSGGDPE IVTHSFNCGG EFFYCNSTQL FNSTWFNSTW STEGSNNTEG SDTITLPCRI 421 KQIINMWQKV GKAMYAPPIS GQIRCSSNIT GLLLTRDGGN SNNESEIFRP GGGDMRDNWR 481 SELYKYKVVK IEPLGVAPTK AKRRVVQREK RAVGIGALFL GFLGAAGSTM GAASMTLTVQ 541 ARQLLSGIVQ QQNNLLRAIE AQQHLLQLTV WGIKQLQARI LAVERYLKDQ QLLGIWGCSG 601 KLICTTAVPW NASWSNKSLE QIWNHTTWME WDREINNYTS LIHSLIEESQ NQQEKNEQEL 661 LELDKWASLW NWFNITNWLW YIKLFIMIVG GLVGLRIVFA VLSIVNRVRQ GYSPLSFQTH 721 LPTPRGPDRP EGIEEEGGER DRDRSIRLVN GSLALIWDDL RSLCLFSYHR LRDLLLIVTR 781 IVELLGRRGW EALKYWWNLL QYWSQELKNS AVSLLNATAI AVAEGTDRVI EVVQGACRAI 841 RHIPRRIRQG LERILL
Appropriate correction is required.
Claim Objections
Claims 1 and 15 are objected to because of the following informalities: the first recitation of an abbreviation in a claim set should be preceded by the unabbreviated form of the term (e.g. human immunodeficiency virus type 1 (HIV-1); messenger ribonucleic acid (mRNA); lipid nanoparticles (LNPs)). Appropriate correction is required.
Claim 15 is objected to because of the following informalities: “compositum” should be “composition” at line 1. 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 2-17 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 rejected for not properly incorporating essential subject matter and information into the claim.
In the instant case, claim 1 is drawn to a recombinant HIV-1 envelope selected from the envelopes listed in Figure 7, Figure 21 or Table 1.
MPEP § 2173.05(s) discloses that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Further, the claim is indefinite because it is improper to import limitations from the specification into the claims, see MPEP §2111.01.
Additionally, the phrase “selected from the envelopes listed in Figure 1, Figure 21, or Table 1” is further indefinite because it is unclear from the phrasing of the claims and the data regarding the figures or tables whether the claim is limited to the exact amino acid sequence as shown in the figures, the construct names listed in Table 1, the full IDs listed in Table 1, the parent construct modified by the listed mutations, or additional unlisted amino acid changes allegedly determinable by a skilled artisan as noted at ¶[0142][0155]. The specification at ¶[0142][0155] characterizes Tables 1a/1b and Figs. 7 and 21 as “non-limiting embodiments,” and Table 1 states that additional changes can be determined at selected positions. Accordingly, the exact metes and bounds of the envelope protein claimed are unclear.
The specification at Table 1 states that the amino acid sequences depicted in Fig. 7 do not include a signal peptide sequence, and that a skilled artisan can identify a suitable signal peptide for expression. From that wording in the Table, it is unclear whether claim 1 is limited to the mature envelope proteins lacking signal peptides, or any envelope construct having any suitable signal peptide.
Finally, “envelope” as used in the claim is not the proper structural term. In context, the application uses “envelope”, “envelope protein”, “Env”, “gp120”, “SOSIP protomers”, “trimers”, and nanoparticle-displayed trimers in overlapping ways. The abstract and technical field describe “immunogenic compositions comprising envelope proteins” [emphasis added] while the claim recites “a recombinant HIV-1 envelope”[emphasis added], which refers to the structure of the overall viral virion itself, and not the protein subunits that form said envelope. As the specification uses multiple terminologies for what appears to be the same thing, one of skill in the art would not be reasonably apprised as to the metes and bounds of the claimed invention.
Since the exact sequences of the envelope proteins within Figures 7 and 21 and Table 1 are known, one suggestion is to amend the claims to recite the specific sequences using the appropriate SEQ ID NOs: along the lines of the following:
“1. A recombinant HIV-1 Env polypeptide, wherein said polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 13-107.”
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 1 is rejected on the grounds of being indefinite. Claims 2-17 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claims 4-9 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 4 recites a composition comprising a nanoparticle and a carrier, wherein the nanoparticle comprises any one of the envelopes of claim 1. Claim 6 similarly recites a composition comprising a nanoparticle and a carrier, wherein the nanoparticle comprises any one of the trimers of claim 2. However, the claims do not clearly define the structural relationship between the recited HIV-1 envelope or trimer and the nanoparticle. It is unclear whether the envelope or trimer is fused to a nanoparticle scaffold, covalently conjugated to the nanoparticle, displayed on the nanoparticle surface, encapsulated within the nanoparticle, adsorbed onto the nanoparticle, or merely present in a composition that also includes nanoparticles. Accordingly, the metes and bounds of claims 4-9 are unclear.
Additionally, claims 5 and 7-9 have the further structural limitations of being with a ferritin nanoparticle which is a self-assembling nanoparticle, but does not identify how the HIV-1 envelope or trimer is structurally associated with the ferritin self-assembling nanoparticle. Ferritin can self-assemble into nanoparticles independently of the HIV-1 envelope or trimer. Therefore, reciting a ferritin self-assembling nanoparticle does not clarify whether the claimed composition requires an Env-ferritin fusion protein, a ferritin nanoparticle displaying Env trimers, an Env trimer conjugated to ferritin, an Env protein encapsulated within or adsorbed onto ferritin, or some other structural arrangement.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claims 4 and 6 are rejected on the grounds of being indefinite. Claims 5 and 7-9 are also rejected since they depend from claim 4 or 6, but do not remedy these deficiencies of claims 4 or 6.
Claim 6 and dependent claims 7-9 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 6 is drawn to a composition comprising a nanoparticle and a carrier, wherein the nanoparticle comprises any one of the trimers of claim 2. Claim 6 depends upon claim 2, which recites “a composition comprising the Env polypeptide of claim 1 and a carrier, wherein the Env polypeptide is a protomer comprised in a trimer”. There is insufficient antecedent basis for the limitation of “trimers” in claim 6, as claim 2 only refers to trimers in the singular.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 6 is rejected on the grounds of being indefinite. Claims 7-9 are also rejected since they depend from claim 6, but do not remedy these deficiencies of claim 6.
Claims 1-17 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the sequences of claim 1, namely the sequences found in Figures 7 and 21 and Table 1, which appear to correspond to SEQ ID NOs: 13-122 but it is not clear if said Env sequences are only confined to these SEQ ID NOs: (see 35 USC 112b rejection supra) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claim 1 recites “[a] recombinant HIV-1 envelope selected from the envelopes listed in Fig. 7, Fig. 21, or Table 1.” The application describes Table 1, Fig. 7, and Fig. 21 as including non-limiting embodiments of envelope designs and amino acid sequences comprising encounter amino acid changes (¶[0055]). The application further states that the envelope designs comprise amino acid changes at antibody-envelope encounter sites/residues and that such changes improve binding of these envelopes to antibodies compared to an unmodified parental sequence (¶[0005][0032]). The application also states that the selected combination comprise envelopes providing representation of sequence/genetic and antigenic diversity of HIV-1 envelope variants that lead to induction of V3 glycan antibody lineages (¶[0015])
The Markush grouping of claim 1 is improper because the alternatives defined by the grouping do not share both a single structural similarity and a common use as required for a proper Markush group. Although the listed alternatives are generally HIV-1 Env mutant sequences, the claim encompasses a large number of distinct engineered Env mutants having different mutation combinations, different antibody-envelope encounter residue changes, and different antigenic/antibody binding properties. The specification does not establish that all of the listed alternatives are functionally equivalent for the claimed immunological purpose. To the contrary, the specification distinguishes the alternatives based on their antibody-binding behavior, encounter residue modifications, antigenic diversity, and intended ability to induce particular antibody lineages. For example, the specification describes the inventive envelope designs as mutations of antibody contact residues selected to improve antibody binding, and separately states that selected combinations of envelopes provide sequence and antigenic diversity relevant to V3 glycan antibody lineages (¶[0005][0015-0016][0021-0023].)
The mere fact that the alternatives are all HIV-1 Env-related sequences does not establish a proper Markush grouping. The relevant inquiry is not whether the alternatives can be placed under the broad label of “HIV-1 Env”, but whether the alternatives are members of a recognized class expected to behave in the same way in the context of the claimed invention, or whether they share a substantial structural feature that is essential to the common use. Here, the specification clearly indicates that the particular amino acid substitutions at antibody-envelope encounter sites materially affect antibody recognition and binding. Therefore, the claimed alternatives are not shown to behave in the same way in the context of the claimed immunogenic compositions and methods.
Accordingly, the members of the Markush group are not shown to be functionally equivalent alternatives for the same use. The common characterization of the sequences as “HIV-1 envelopes” or “HIV-1 Env mutant sequences” is insufficient because the common use asserted by the specification is not merely that the proteins are Env proteins, but that the specific engineered Env designs provide defined immunological/antigenic properties, including altered antibody binding and induction of anti-HIV-1 antibody responses. The data provided within the specification and the description of the sequences indicated that the listed Env mutants are immunologically distinct alternatives rather than interchangeable members of a single functionally equivalent class.
Claims 2-17 depend directly or indirectly from claim 1 or otherwise recite compositions, nanoparticles, nucleic acids, pharmaceutical compositions, or methods using the recombinant envelopes of claim 1. For this reason and for the further 35 USC 112a and 35 USC 112b issues regarding the claims, claims 2-17 are also included within this rejection.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a recombinant human immunodeficiency virus type 1 (HIV-1) envelope (Env) polypeptide, wherein said polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 13-107.
Claim 2 is drawn to a composition comprising the Env polypeptide of claim 1 and a carrier, wherein the Env polypeptide is a protomer comprised in a trimer.
Further limitations on the composition of claim 2 are wherein the Env polypeptide is CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A (HV1302206_N442A or HV1301345_T238K_E241T_N353K_N442A, ¶[0154])(claim 3)
Claim 4 is drawn to a composition comprising a nanoparticle and a carrier, wherein the nanoparticle comprises any one of the Env polypeptides of claim 1.
Further limitations on the composition of claim 4 are wherein the nanoparticle is a ferritin self- assembling nanoparticle (claim 5).
Claim 6 is drawn to a composition comprising a nanoparticle and a carrier, wherein the nanoparticle comprises any one of the trimers of claim 2.
Further limitations on the composition of claim 6 are wherein the nanoparticle is a ferritin self- assembling nanoparticle (claim 7), wherein the nanoparticle comprises multimers of trimers (claim 8), wherein the nanoparticle comprises 1 to 8 trimers (claim 9).
Claim 10 is drawn to a method of inducing an immune response in a subject comprising administering in an amount sufficient to affect such induction an immunogenic composition comprising any one of the recombinant HIV-1 Env polypeptides of claim 1.
Further limitations on the method of claim 10 are wherein the composition is administered as a prime (claim 11) or a boost (claim 12).
Claim 13 is drawn to an isolated nucleic acid encoding any of the recombinant HIV-1 Env polyproteins of claim 1.
Claim 14 is drawn to a composition comprising the nucleic acid of claim 13 and a carrier.
Further limitations on the composition of claim 14 are wherein the nucleic acid is modified messenger ribonucleic acid (mRNA) formulated in lipid nanoparticles (LNPs)(claim 15).
Claim 16 is drawn to a method of inducing an immune response in a subject comprising administering in an amount sufficient to affect such induction an immunogenic composition comprising the nucleic acid of claim 13.
Further limitations on the method of claim 16 are wherein the composition is administered as a boost (claim 17).
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.
Claim 3 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A (also called “HV1302206_N442A” or “HV1301345_T238K_E241T_N353K_N442A”, ¶[0154]) is required to practice the claimed invention because it is a claimed Env polypeptide construct. As a required element it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification, or otherwise readily available to the public. If it is not so obtainable or available, the enablement requirements of 35 U.S.C. § 112, first paragraph, may be satisfied by a deposit of CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A. See 37 CFR 1.802. One cannot practice the claimed invention without CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A. Therefore, access to CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A is required to practice the invention. The specification does not provide a repeatable method for readily identifying CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A without access to CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A and it does not appear to be readily available material.
One way of overcoming this rejection is if CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A has an associated SEQ ID NO: already deposited with the instant application, identification of said SEQ ID NO: would satisfy the deposit requirement to enable said polypeptide. At ¶[0006] of the specification, it is noted that “CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238K_E241T_N408K_N442A” is also referred as “HV1302206_N442A”; however, at p. 31 of the drawings submitted on 07/28/2023, there is a sequence at the top of the page listed as “HV1302206_N442A” but it appears to correspond to “HV1301345_T238K_E241T_N353K_N442A”[emphasis added], which does not comprise the same mutations. Therefore, it is unclear if there is a SEQ ID NO: that is associated with this sequence in the specification.
If a SEQ ID NO: is not available, deposit of CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_T238KE241T_N408KN442A in a recognized deposit facility would satisfy the enablement requirements of 35 U.S.C. 112, because the strains would be readily available to the public to practice the invention claimed, see 37 CFR 1.801- 37 CFR 1.809.
If a deposit is made under the terms of the Budapest Treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made under the terms of the Budapest Treaty and that all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of a patent, would satisfy the deposit requirements. See 37 CFR 1.808.
If a deposit is not made under the terms of the Budapest Treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made at an acceptable depository and that the following criteria have been met:
(a) during the pendency of this application, access to the invention will be afforded to one determined by the Commissioner to be entitled thereto;
(b) all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon granting of the patent;
(c) the deposit will be maintained for a term of at least thirty (30) years and at least five (5) years after the most recent request for the furnishing of a sample of the deposited material;
(d) a viability statement in accordance with the provisions of 37 CFR 1.807; and
(e) the deposit will be replaced should it become necessary due to inviability, contamination or loss of capability to function in the manner described in the specification.
In addition the identifying information set forth in 37 CFR 1.809(d) should be added to the specification. See 37 CFR 1.803 - 37 CFR 1.809 for additional explanation of these requirements.
Claims 13-14 and 16-17 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 isolated nucleic acids and compositions/methods of use thereof, does not reasonably provide enablement for any nucleic acid in any composition for use in any method. 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 claim is directed broadly to “a nucleic acid” without limitation as to form, environment, or method of use. As such, the claim encompasses the nucleic acid in a wide range of contexts, including incorporation into vectors, plasmids, artificial chromosomes (e.g. bacterial or yeast artificial chromosomes (BACs or YACs)), cosmids, prokaryotic and eukaryotic cells, and organismal systems (e.g. Bacteria and Archaea, Eukaryotes (including vertebrate and invertebrate animals, plants, and fungi), and viruses).
The specification does not provide guidance sufficient to enable the use of the claimed nucleic acid across this full scope, including in complex biological systems where expression, stability, and functionality may vary depending on the host environment and delivery method.
Accordingly, undue experimentation would be required to determine how to make and use the claimed nucleic acid across the full scope of the claim. It is suggested that the claim be amended to read upon “an isolated nucleic acid” [emphasis added] in order to overcome this rejection.
Claims 10-12 and 16-17 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 selected recombinant HIV-1 Env “encounter” designs and selected immunization studies, does not reasonably provide enablement for the full scope of the method of inducing any immune response in any subject using any of the recombinant HIV-1 envelopes of claim 1 or nucleic acids encoding any of the recombinant envelopes of claim 1. 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.
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 methods of inducing an immune response in a subject by administering immunogenic compositions comprising any one of the recombinant HIV-1 envelopes of claim 1, or nucleic acids encoding any of the recombinant HIV-1 envelopes of claim 1.
Claim 10 recites a method of inducing an immune response in a subject comprising administering an immunogenic composition comprising any one of the recombinant envelopes of claim 1. Claims 11 and 12 further recite that the composition is administered as a prime or a boost. Claim 16 recites a similar method, except any nucleic acid encoding any of the recombinant envelopes of claim 1 is administered, and claim 17 notes that said nucleic acid may be administered as a boost.
The claims are broad because they are not limited to a particular Env sequence, immunogen format, dose, adjuvant, route of administration, immunization schedule, subject type, antibody lineage, immune-response endpoint, antibody specificity, neutralization breadth, or magnitude of immune response. Claim 1 broadly refers to recombinant HIV-1 envelopes listed in Figs. 7 and 21 and Table 1, and the description indicates that these numerous “encounter-design” mutants have different amino acid changes and different antibody binding effects (¶[0005][0032][0036-0038][0055][0059][0064][0140][0142][0155][0157-0160][0164-0165]).
The breadth is especially significant because the claimed result is not merely making an Env polypeptide; the claimed result is inducing an immune response in a subject. Whether a particular Env mutant, formulation, nucleic acid, construct, dose, route, prime/boost sequence, or subject will induce the desired immune response is a biological and immunological outcome that is highly variable depending on the testing scenario. The specification itself frames the invention around precise antibody/envelope encounter states, affinity/association rate changes, and selection of specific antibody lineage mutations rather than a simple interchangeable set of Env proteins. The specification notes that the designs were selected to stabilize or alter collision-induced encounter states and to improve antibody association rates by modifying antibody/envelope encounter residues (¶[0160-0191]).
State of the prior art/Predictability of the art. The state of the prior art supports a finding that the full scope of the claimed methods would not have been predictable. HIV-1 Env vaccine design was known to be complex and unpredictable because Env is highly variable, heavily glycosylated, conformationally sensitive, and capable of eliciting off-target or strain-limited immune responses. Prior reviews described Env trimer nanoparticle display as a promising strategy, but also recognized that antigenicity, epitope presentation, B-cell activation, neutralization breadth, and immunization outcome depend on trimer design, scaffold/nanoparticle format, valency, spacing, adjuvant(s), and immunization regimen (Brinkkemper M, et. al. Vaccines (Basel). 2019 Jul 29;7(3):76.). Brouwer et. al. (Brouwer PJM, et. al. Curr Opin HIV AIDS. 2019 Jul;14(4):302-308.) reviewed Env trimer nanoparticles and described nanoparticle display as a way to enhance immune responses, but the reference also reflects that Env trimer nanoparticle vaccine design remained an active optimization problem rather than a predictable plug-and-play platform.
The unpredictability is heightened for the V3-glycan/broadly-neutralizing antibody (bnAb)-lineage context of this application. The specification itself states that N322 glycan targeting bnAbs are “common yet quite diverse”, and that different V3-glycan bnAbs use different heavy and light chain genes and different angles of approach in the bound configuration (¶[0161]). The specification further states that designs aimed at eliciting bnAb responses had shown some promise but had not yet elicited a consistent bnAb response (¶[0161-0166]). This admission is consistent with the art: Henderson et. al. (Henderson R, et. al. Nat Commun. 2024 Nov 3;15(1):9503.) explains that V3-glycan bnAb lineages vary in gene usage and antibody contacts, and that the heterogeneous nature of individual antibody contacts and orientations complicates vaccine immunogen development.
The ferritin/nanoparticles and mRNA/LNP aspects were also unpredictable across the full scope. Prior work showed that ferritin nanoparticles could display HIV-1 Env trimers and improve immunogenicity compared with soluble trimers, but such work involved particular Env/scaffold designs rather than any Env mutant and any nanoparticle/ferritin arrangement. Sliepen et. al. (Sliepen K, et. al. Retrovirology. 2015 Sep 26;12:82.) reported ferritin-based nanoparticles displaying multiple copies of native-like BG505 SOSIP.664 trimers, and Brouwer reviewed Env trimer nanoparticle display approaches. The instant specification also acknowledges this unpredictability by stating that ferritin alone readily forms 24-subunit nanoparticles, but appending ferritin to Env “only yields nanoparticles for certain envelopes” because Env can interfere with ferritin folding or subunit association (¶[0128]).
For nucleic acid and modified mRNA/LNP embodiments, the art did not establish that any nucleic acid encoding any of the claimed Env mutants would predictably induce an immune response in the subject. The application itself states that additional studies “will” be performed using mRNA versions of the constructs to determine whether mRNA vaccination is more effective in selecting particular antibody mutations compared to protein immunization (¶[0195]). Post-filing publications further illustrate that mRNA-encoded Env-ferritin constructs require empirical optimization and do not automatically behave like corresponding protein immunogens. For example, Mu et. al. (Mu Z, et. al. Cell Rep. 2022 Mar 15;38(11):110514.) reported that mRNAs can encode antigenic Env trimer ferritin nanoparticles in mice, while later work reported that well-folded Env-ferritin nanoparticles were only a minority of the protein expressed by an mRNA design and showed dose-dependent and/or minimal immunogenicity under certain conditions (Mu Z, et. al. J Virol. 2024 Sep 17;98(9):e0013724. Epub 2024 Aug 13.)
Working examples. Disclosed in the specification are working examples for selected constructs and selected assays, but such examples are not commensurate in scope with the breadth of the instant claims.
The examples focus on selected HIV-1 Env encounter designs and selected antibody lineage binding/kinetic studies. For example, the specification describes results for selected CH848_SOSIP-DH270 lineage Fab kinetics, including selected constructs showing roughly two-fold improvements in association rate relative to parent constructs (Figs. 11-20). The specification also describes IA4 or UCA3 knock-in mouse studies involving CH848 10.17 and an encounter design, along with serum binding and blocking results (Figs. 25-29). Specifically, FIG. 34 demonstrates that HV1302206_N442A vaccinated mice elicit antibodies which are superior to neutralizing critical, improbable mutants (¶[0194]), and future nanoparticle/nucleic acid prime/protein boost studies will be performed to determine how the heterologous prime/boost model elicits antibodies (¶[0195]).
However, claims 10-12 and 16-17 are not only limited to the tested constructs, tested animal model, tested immunization scheme, tested protein composition, tested prime/boost context, or tested antibody lineage. The examples do not show that each recombinant Env encompassed by claim 1, or each nucleic acid type (e.g. plasmid, vector, mRNA, DNA, ssRNA, dsRNA, BAC/YAC, etc.) encoding such an envelope, induces an immune response in any subject across the full scope of the claims. The specification also does not provide working examples demonstrating that modified mRNA delivered by LNPs of all claimed Env mutants induced the same therapeutic immune response. Instead, the specification provides only prophetic guidance stating that such studies will be performed in the future (¶[0195]).
Guidance in the specification. The specification provides guidance towards designing selected HIV-1 Env encounter mutants intended to modify antibody association pathways and binding kinetics. It explains that certain designs were chosen based on N332 glycan states, V4 loading states, electrostatic or polar complementarity, and encounter-site alanine mutations. Accordingly, the guidance is insufficient to enable the full scope of the claimed methods. The specification does not provide a predictive rule by which a skilled artisan could determine, without undue experimentation, which of the numerous Env mutants, formulations, nucleic acid constructs, mRNA/LNP designs, doses, routes, adjuvants, prime/boost schedules, or subjects would induce the claimed immune response. Nor does the specification provide a generalizable correlation showing that improved binding to selected DH270-lineage antibodies, or improved association rates in vitro, necessarily produces an immune response in any subject when administered as a protein, nucleic acid, prime, or boost.
The guidance is particularly insufficient for claims 16 and 17 in that nucleic acid administration introduces additional variables including nucleic acid format, codon design, untranslated regions, signal peptide/leader sequence, expression level, lipid nanoparticle formulation, tissue expression, antigen folding, glycosylation, trimerization, nanoparticle assembly (if applicable), and in vivo presentation. The specification identifies “modified mRNA” as the subject of future studies without identifying what type of modifications are performed to said mRNA and fails to provide any evidence of embodiments across the full scope of the claims.
Amount of experimentation necessary. Additional research is required in order to determine how effective each claimed Env mutant or encoded nucleic acid is for inducing an immune response in a subject. A skilled artisan would need to synthesize or express the relevant Env mutant or nucleic acid, confirm expression, folding, glycosylation, trimerization, antigenicity, stability, and formulation compatibility, select the dose, route of administration, appropriate carriers/excipients/adjuvants, and prime/boost schedule, administer to appropriate animal models and/or subjects, and then test binding, B-cell lineage activation, serum responses, neutralization, and/or other immune-response endpoints.
For the nucleic acid claims, the experimentation would further require preparing and optimizing nucleic acid constructs, including modified mRNA in multiple types of LNP embodiments, and determining whether each construct expresses an antigenically proper Env protein in vivo and induces the claimed immune response.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.
In the instantly claimed invention, the claims encompass methods of inducing an immune response using any of numerous recombinant HIV-1 Env mutants and any nucleic acid encoding them, without limiting the claims to the specific constructs, formulations, animal models, routes, doses, schedules, or immune-response endpoints that were actually tested. The specification provides only selected, limited examples and design principles, but does not provide a roadmap enabling the full claimed scope. Determining which embodiments within the full claim scope induce the claimed immune response would require synthesis, formulation, administration, and immunological screening across a large number of candidate Env designs and delivery formats
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods commensurate in scope with claims 10-12 and 16-17.
Claims 4-9 and 15 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 specific, disclosed Env-ferritin or Env nanoparticle concepts, does not reasonably provide enablement for any nanoparticles comprising in any fashion any one of the recombinant envelopes of claim 1 or any one of the trimers of claim 2. 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 compositions comprising nanoparticles and carriers, wherein the nanoparticle comprises any one of the envelopes of claim 1 or any one of the trimers of claim 2. Claims 5 and 7 further recite that the nanoparticle is a ferritin self-assembling nanoparticle (also known as SANPs). Claim 8 recites that the nanoparticle comprises multimers of trimers, with claim 9 reciting that there are 1-8 trimers. Claim 15 is drawn to a composition comprising a nucleic acid encoding any of the Env polypeptides of claim 1, wherein said nucleic acid is any “modified mRNA” and is formulated in any lipid nanoparticle (LNP).
The claims are broad because they are not limited to a particular nanoparticle type, and even with further dependent claims limiting the nanoparticle to either a LNP or ferritin SAPN, there is still considerable breadth with regards to the ferritin species, ferritin sequence, Env-ferritin fusion orientation, linker sequence, linker length, conjugation chemistry, LNP lipid ratio/makeup, surface display arrangement, valency, spacing, encapsulation/adsorption/fusion mechanism for the payload (e.g. the Env polypeptide or nucleic acid), expression system, purification method, folding/assembly condition, or antigenicity requirement. As set forth supra with respect to the 35 USC 112b rejections, the breadth of claim 6 is drawn to any nanoparticle that “comprises” the Env trimer of claim 2 in any fashion. While claims 5 and 7 narrow the nanoparticle to ferritin, these claims still do not require a particular structural relationship between the Env trimer and ferritin.
“Modified mRNA” is interpreted as any modification that may be made to mRNA. The specification notes some modifications, such as the use of modified nucleosides such as 1-methyl-pseudouridine (¶[0012]), the use of 3’ poly-A tails or 5’ caps (¶[0027]), and other modifications known in the art (¶[0083-0084]). Further modifications that can reasonably read upon this are RNA splicing, chemical modifications to the bases themselves such as N6-methyladenosine, 5-methylcytosine, pseudouridine, and N1-methyladenosine, codon optimization and/or G/C enrichment, and the use of untranslated regions (UTRs).
“Lipid nanoparticles” are any microscopic, spherical vesicles made of fat molecules used as delivery vehicles for biological payloads, such as nucleic acid. LNPs are typically composed of four main ingredients, namely an ionizable lipid, a structural component (usually cholesterol), helper/neutral lipids (aid in structural integrity and fusion with target cell membrane), and PEGylated lipids to shield the LNP from the host immune response.
The breadth is material because successful nanoparticle formulation, ferritin display, and LNP-mediated modified mRNA expression are not inherent results of merely reciting a nanoparticle, ferritin SAPN, or LNP. For ferritin, this specification acknowledges that the inventive envelope designs may include linkers between Env and ferritin designed to optimize ferritin nanoparticle assembly (¶[0126-0135]). For LNPs, the specification broadly states that the nucleic acid may be mRNA, modified or unmodified, and formulated in lipids such as LNPs, but does not provide sufficient formulation guidance showing that modified mRNA encoding any of the claimed Env proteins can be formulated in LNPs and used across the full claim scope.
State of the prior art/Predictability of the art. The state of the prior art supports a finding that Env nanoparticle formulation, Env-ferritin nanoparticle formation, and LNP-mediated modified mRNA delivery were not predictable across the full scope of the claims.
Prior art established that HIV-1 Env trimers could be presented on ferritin nanoparticles, but such disclosures used defined Env constructs and defined ferritin display strategies. Sliepen (supra) reported ferritin-based protein nanoparticles displaying multiple copies of native-like BG505 SOSIP.664 Env trimers, and Brouwer (supra) reviewed HIV-1 Env trimer nanoparticle vaccine approaches. Those references as discussed here and supra show that Env nanoparticle display was an active design field involving scaffold selection, trimer stabilization, antigenic presentation, and multivalent display, not a predictable result for any Env mutant and any nanoparticle format.
The unpredictability in the ferritin art is also supported directly by the specification, which frames ferritin nanoparticle embodiments in terms of Env-ferritin linker optimization. The application states that inventive envelope designs may include linkers between Env and ferritin designed to optimize ferritin nanoparticle assembly (¶0128]). That disclosure indicated that successful Env-ferritin nanoparticle assembly depends on structural design choices, not merely on the fact that ferritin can self-assemble.
The LNP and modified mRNA components are equally unpredictable. mRNA-LNP delivery is a multi-component delivery technology in which expression and immunogenicity depend on the mRNA construct (e.g. G/C enrichment, UTRs, chemical modifications to bases, 5’ caps, 3’ polyA tails, etc.) and LNP formulation (e.g. type of ionizable lipid used, such as cationic ionizable lipid, molar ratio of lipid components in LNP, charge formulation between mRNA and LNP, etc.) Reviews in the field identify LNPs as multi-component systems which typically include ionizable lipids, helper lipids/phospholipids, cholesterol, and PEGylated lipids, with delivery depending on parameters such as RNA encapsulation, particle size, lipid composition, stability, cellular uptake, endosomal escape, tissue biodistribution, and protein expression. Hou et. al. (Hou X, et. al. Nat Rev Mater. 2021;6(12):1078-1094. Epub 2021 Aug 10.) details LNP design for mRNA delivery and details the empirical testing which must be performed with respect to the stability of the compositions, the physiological barriers encountered by the system, and administration routes of the compositions, while Pardi et. al. (Pardi N, et. al. Nat Rev Drug Discov. 2018 Apr;17(4):261-279. Epub 2018 Jan 12.) explains that mRNA vaccines require effective delivery systems and that lipid nanoparticles recently became one of the most appealing and commonly used mRNA delivery tools, and that the magnitude and duration of the immune response elicited varies depending on the route of administration.
LNP technology was not predictable merely because LNPs were known. The art recognized that LNP formulation variables materially affect delivery performance. For example, LNP-mediated mRNA delivery requires protection of the RNA, cellular uptake, endosomal escape, cytosolic release, and translation, and ionizable lipid structure and formulation composition are central to these functions. Later reviews of the technology summarize that ionizable lipids are important for complexing with negatively charged mRNA and facilitating endosomal escape, and that LNP performance depends on lipid composition and formulation parameters (Swetha K, et. al. Vaccines (Basel). 2023 Mar 14;11(3):658.; Yang L, et. al. Pharmaceutics. 2022 Dec 1;14(12):2682.) These references are consistent with the state of the art that a skilled artisan, prior to and after the filing date of the instant invention, could not simply select any modified mRNA encoding any large HIV-1 Env protein and any LNP and reasonably expect successful formulation, delivery, expression, antigen folding, trimerization, glycosylation, and immunogenic presentation across the full claim scope.
This unpredictability is especially relevant here because HIV-1 Env is a conformationally sensitive, heavily glycosylated antigen. Modified mRNA-LNP delivery of an Env antigen does not merely require mRNA entry into cells; it also requires expression of a properly folded, processed, glycosylated, and immunologically relevant Env protein. The instant specification itself treats mRNA embodiments as future studies, stating that mRNA versions of the constructs will be tested to determine whether mRNA vaccination is more effective than protein immunization in selecting particular antibody mutations (¶[0194]). That statement alone confirms that the full scope of claim 15 has not been demonstrated.
Working examples. The specification provides selected and limited disclosure concerning ferritin nanoparticles, Env nanoparticles, nucleic acids, modified mRNA, and LNPs, and fails to provide working examples commensurate in scope with the limitations of instant claims 4-9 and 15.
With respect to claims 4-9, the disclosure fails to demonstrate that each recombinant HIV-1 Env polypeptide listed in Fig. 7, Fig. 21, or Table 1 can be incorporated into any nanoparticle. It does not demonstrate that each such Env polypeptide can be fused to ferritin, conjugated to ferritin, displayed on ferritin, or otherwise structurally associated with ferritin while maintaining proper nanoparticle assembly. It also does not demonstrate that each trimer of claim 2 can be incorporated into a nanoparticle comprising multimers of trimers or 1-8 trimers. The specification provides only prophetic guidance regarding such structures and notes that said studies will be performed in the future (¶[0194]).
With respect to claim 15, the specification fails to provide any working examples showing any production of any modified mRNA encoding any of the recombinant HIV-1 Env polypeptide listed in Fig. 7, Fig. 21, or Table 1, nor does the specification provide any working examples in relation to any LNPs which may encapsulate said modified mRNA. The specification provides only prophetic guidance regarding such structures and notes that said studies will be performed in the future (¶[0194]).
Guidance in the specification. The specification provides limited guidance towards selected ferritin nanoparticle designs, selected Env encounter designs, and general nucleic acid/LNP embodiments. For example, the specification states that the nucleic acid may be mRNA, and that mRNA may be encapsulated or formulated in LNPs. However, the guidance is insufficient for the full scope of the claimed invention. With respect to claims 4-9, the claims are not limited to the disclosed fusion arrangement, linker types, linker lengths, ferritin species, ferritin sequence, ferritin attachment position, or conjugation strategy. The specification broadly refers to nanoparticle and ferritin embodiments, but does not provide a predictive rule allowing a skilled artisan to determine what linkers, ferritin sequences, attachment positions, Env mutants, or trimer formats will successfully assemble into antigenically proper nanoparticles. With respect to claim 15, the specification fails to provide adequate formulation guidance for modified mRNA encoding any of the claimed HIV-1 Envs formulated in LNPs, and does not provide predictive rules allowing a skilled artisan to determine what ionizable lipid, helper/neutral lipid, cholesterol content, PEGylated lipid, lipid molar ratio, mRNA-to-lipid ratio, particle size, encapsulation efficiency, buffer, manufacturing process, route, dose, or other formulation parameters are necessary to delivery any nucleic acid encoding any of the claimed Env. Accordingly, the disclosure provides a general research direction rather than enablement commensurate with the full breadth of the claims.
Amount of experimentation necessary. Additional research is required in order to determine how to make and use nanoparticles, such as ferritin or LNPs, comprising the Env as claimed.
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, for each Env mutant or trimer encompassed by the claims, a skilled artisan would need to design and produce a nanoparticle construct, determine whether the Env is fused, conjugated, displayed, encapsulated, adsorbed, or otherwise associated with the nanoparticle, select a scaffold or ferritin species, select linker sequences and length, select attachment site/orientation to ensure relevant Env epitopes are displayed and not masked, confirm Env folding and trimerization, confirm antigenic presentation, and determine whether the resulting nanoparticle is suitable for the claimed immunogenic composition. For the mRNA/LNP compositions, a skilled artisan would need to design or obtain modified mRNA encoding a representative number of claimed Env sequences, optimize codon usage, UTRs, 5’ caps, 3’ polyA tails, modified nucleoside composition, signal peptide/leader sequences, antigen coding sequence, and then formulate said modified mRNA into LNPs by selecting lipid components, lipid ratios, lipid species, particle size, encapsulation efficiency, and manufacturing conditions. The skilled artisan would need to further determine whether each LNP formulation successfully delivers and encodes the mRNA, and if it produces an immunologically relevant Env product. Given the number of claimed Env sequences, and the number of nanoparticle variables, the claims would require substantial empirical screening and optimization.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed nanoparticles.
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 1-2 and 4-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haynes et. al. (WO2018161049A1; Pub. 09/07/2018; hereafter “Haynes”.)
The Prior Art
Haynes teaches HIV-1 immunogens, including envelopes (CH0848) and selections therefrom, and methods for swarm immunizations using combinations of HIV- 1 envelopes (entire document; see abstract.) Haynes teaches SEQ ID NOs: 325, 493, 491, and 507, which are sequences that comprise an Env protein that is 100% identical to instant SEQ ID NO: 13 (¶[0087][0092][0094]; Figs. 39, 45, 47; instant claim 1.) Haynes teaches that said Env may be within a composition comprising a carrier, wherein the Env polypeptide is a promoter that is comprised in a trimer (¶[0032][0038][0150]; reference claims 1-2, 4; instant claim 2). Haynes teaches the Env polypeptide may be CH848.3.D0949.10.17CHIM.6R.SOSIP.664V4.1 (¶[0041][0089]) and may comprise further mutations. Haynes teaches the Env polyprotein may be within compositions which further comprise nanoparticles (¶[0017]; instant claims 4, 6), such as ferritin self-assembling nanoparticles (¶[0142][0415]; Fig. 77E; instant claims 5, 7), wherein each ferritin can have 6 Env trimers (¶[0415]; instant claims 8-9). Haynes teaches methods of inducing an immune response in a subject comprising administering a composition comprising an HIV-1 envelope polypeptide in an amount sufficient to induce an immune response (reference claim 8; instant claim 10). Said compositions may be administered in a prime/boost vaccination regimen (¶[0008]; instant claims 11-12). Haynes teaches nucleic acids encoding the recombinant HIV-1 Env polypeptides (reference claim 3; instant claim 13), and immunogenic compositions comprising said nucleic acid and a carrier (reference claim 5; instant claim 14). Haynes teaches the nucleic acid may be in the form of modified mRNA (¶[0159]) wherein said mRNA may be delivered by lipid nanoparticles (LNPs) in order to induce an immune response in a subject (¶[0203]; instant claims 15-16). Haynes teaches that any suitable form of the envelope could be used for prime and/or boost (¶[0008][0372]; instant claim 17).
For at least these reasons, Haynes teaches the limitations of instant claims 1-2 and 4-17, and anticipates the instant invention encompassed by said claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2 and 4-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,318,197. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a recombinant HIV-1 Env polypeptide, wherein reference SEQ ID NOs: 491 (‘197) and instant SEQ ID NO: 13 are 100% identical (NB: SEQ ID NO: 491 is present in further dependent claims, as this is an example of a sequence which comprises the structural elements of reference claim 1). Both sets of claims are drawn to nucleic acids encoding the Env polypeptide, and compositions comprising said nucleic acid and a carrier. Both sets of claims are drawn to the Env polypeptide in a composition comprising a carrier. While the ‘197 claims further provide for adjuvants and the nucleic acid to be within an expression vector driven by a promoter, such modifications would be obvious to a skilled artisan and are not patentably distinct limitations. Both sets of claims provide that the Env polypeptide is multimerized and within a liposome or nanoparticle, such as a ferritin nanoparticle. Both sets of claims provide methods of inducing an immune response in a subject through administration of a composition comprising said Env polypeptide or a nucleic acid encoding said Env polypeptide.
For at least these reasons, the instant claims and the ‘197 claims are not patentably distinct.
Claims 1-2 and 4-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-19 of U.S. Patent No. 11,246,920. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a recombinant HIV-1 Env polypeptide, wherein reference SEQ ID NOs: 491 (‘920) and instant SEQ ID NO: 13 are 100% identical. Both sets of claims are drawn to nucleic acids encoding the Env polypeptide, and compositions comprising said nucleic acid and a carrier. Both sets of claims are drawn to the Env polypeptide in a composition comprising a carrier. While the ‘920 claims further provide for adjuvants and the nucleic acid to be within an expression vector driven by a promoter, such modifications would be obvious to a skilled artisan and are not patentably distinct limitations. Both sets of claims provide that the Env polypeptide is multimerized and within a liposome or nanoparticle, such as a ferritin nanoparticle. Both sets of claims provide methods of inducing an immune response in a subject through administration of a composition comprising said Env polypeptide or a nucleic acid encoding said Env polypeptide.
For at least these reasons, the instant claims and the ‘920 claims are not patentably distinct.
Claims 1-2 and 4-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 26-28 of copending Application No. 18/700,677 (reference application) in view of Saunders (WO2019169356A1, Pub. 09/06/2019; hereafter “Saunders”.) Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to recombinant Env proteins. While the recombinant Env proteins are similar between claims, they do not appear to be identical; however, the teachings of Saunders shows that the Env protein of the ‘677 claims was known in the art at the time of filing, as SEQ ID NO: 87 is 100% identical to HV1301580_D230N_H289N_P291S of reference Table 5, Fig. 29B. Therefore, it would be a simple substitution of a known element in the art, especially as Saunders teaches modified Env for induction of immune responses.
Both the instant claims and the ‘677 claims are drawn to compositions comprising the Env proteins and a carrier, both sets of claims are drawn to stable trimers comprising the Env proteins. Both sets of claims are drawn to compositions comprising the nanoparticles comprising the Env and a carrier, both sets of claims are drawn to compositions comprising nanoparticles, Env trimers, and a carrier. Both sets of claims are drawn to the nanoparticles being ferritin nanoparticles which comprise multiples of Env trimers, such as 1-8 trimers. Both sets of claims are drawn to methods of inducing an immune response in a subject through administration of the Env composition, or compositions comprising nucleic acids encoding said Env. Both sets of claims are drawn to compositions comprising nucleic acids encoding said Env. Both sets of claims are drawn to prime/boost vaccination regimens of the methods. Both sets of claims are drawn to the nucleic acid being mRNA and administered within a LNP. Therefore, given the teachings of the prior art as evidenced by Saunders, the instant claims and the ‘677 claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Wiehe K, et. al. Cell Host Microbe. 2024 May 8;32(5):693-709.e7. Epub 2024 Apr 25. Applicant-related post-filing art that relates to the instant invention.
Mu Z, et. al. Cell Rep. 2022 Mar 15;38(11):110514. Applicant-related post-filing art that relates to the instant invention.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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