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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/3/2025 has been entered.
Election/Restrictions
Applicant’s amendment entered 9/3/2025 is acknowledged.
Applicant’s amendment entered 11/1/2024 is acknowledged. Claims 1, 12, 19, & 25 are canceled.
Applicant’s election without traverse of the required species in the reply filed on 4/16/2024 is acknowledged.
The elected species are:
A specific VH CDR1 sequence: SEQ ID NO: 18.
A specific VH CDR2 sequence: SEQ ID NO: 19.
A specific VH CDR3 sequence: SEQ ID NO: 20.
A specific VL CDR1 sequence: SEQ ID NO: 23.
A specific VL CDR2 sequence: SEQ ID NO: 24.
A specific VL CDR3 sequence: SEQ ID NO: 25.
One or more specific residues at the VH framework regions: G at H15, L at H37, E at H39, T at H40, H at H68, G at H70, H at H72, P at H73, T at H87, A at H88, V at H89, W at H100, E at H101, and K at H105.
One or more specific residues at the VL framework regions: S at L2, Y at L3, V at L4, L at L5, T at L6, Q at L7, P at L8, P at L9, S at L10, V at L11, V at L19, K at L45, I at L68, D at L69, N at L80, T at L88.
A specific VH sequence: SEQ ID NO: 8.
A specific VL sequence: SEQ ID NO: 10.
One or more specific additional therapeutic agent: a second antibody.
The requirement is still deemed proper and is therefore FINAL.
Amended claims 3-4, 18, 60-61, 76, 82, 89-90, 94, 100-104, 106, and 112 are under examination on the merits.
Response to Amendment
Applicant's arguments filed 9/3/2025 regarding the i) written description rejection under 35 U.S.C. § 112a and ii) the scope of enablement rejection of claims 103 and 106 under 35 U.S.C. § 112a have been fully considered but they are not persuasive. See response below.
Applicant’s arguments, see pp. 1-3, filed 9/3/2025, with respect to the previous indefiniteness rejections under 35 U.S.C. § 112(b) have been fully considered and are persuasive. The previous indefiniteness rejections under 35 U.S.C. § 112(b) have been withdrawn.
Applicant’s amendment necessitates new objections to claims 18 and 94, and rejections under 35 U.S.C. §§112(b) and (d), see below.
Objections and Rejections Withdrawn
The previous objections and rejections are hereby withdrawn due to Applicant’s amendment submitted on 9/3/2025:
Claim objections: claim 3 and claim 76.
35 U.S.C. §112(b): claims 3, 4, 18, 60-61, 76, 82, 89-90, 94, 100-104, & 106.
Claim Objections
(New Objection) Claim 18 is objected to because of the following informalities: the claim contains a typographical error on line 2, where “90%sequence identity” should instead read “90% sequence identity”. Appropriate correction is required.
(New Objection) Claim 94 is objected to because of the following informalities: claim 94 has a typographical mistake, where canceled claims 91-93 are described in claim 94. Appropriate correction is required. See below.
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Claim Rejections - 35 USC § 112
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.
(Previous Rejection Maintained) Claims 3, 82, 89-90, 94, & 100 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 claims 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 3 is drawn to an antibody or antigen binding fragment thereof capable of binding HIV gp120, wherein the antibody or antigen binding fragment thereof comprises a VH with VH CDR1, VH CDR2, and VH CDR3, and a VL that comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1 comprises SEQ ID NO: 12 or 18; the VH CDR2 comprises the sequence of SEQ ID NO: 13, 19, or 61; the VH CDR3 comprises the sequence of 14, 20, 21, 22, 59, 60, 62, 67, or 140-144; the VL CDR1 comprises the sequence of SEQ ID NO: 15, 23, or 63; the VL CDR2 comprises the sequence of SEQ ID NO: 16, 24, or 145; and/or the VL CDR3 comprises the sequence of SEQ ID NO: 17, 25, 68, 146, or 147, wherein the antibody or antigen binding fragment does not comprise each of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 12, 13, 14, 15, 16, and 17, respectively. Notably, the claim is quite generic in that it recites an antigen that the antibody or antigen binding fragment thereof can bind, HIV gp120, but each species of the claimed antibody has not been reduced to practice.
In support of the claimed genus of an “an antibody or antigen binding fragment thereof capable of binding HIV gp120,” the specification discloses ePGT-121.15.H1.L1, which exhibited enhanced neutralization breadth and potency of HIV clades, as compared to the parent PGT-121 antibody (paras. [0137]-[0138]; Table 5). The specification also discloses a number of engineered PGT1-121 derivatives, the light chains of which were generated using combinatorial libraries designed by shuffling sequence variation present in PGT-121, PGT-122, PGT-123, PGT-124, PGT-133, and PGT-134 antibodies, from which the ePGT121.L4 VL sequence was selected for further use (Spec., Pages 199-200). Thus, a limited number of derivatives, variants, or mutants thereof are disclosed that can achieve the claimed ability to bind to HIV gp120. Thus, the application fails to provide examples commensurate in scope with the breadth of the claimed genus.
Moreover, the decision arrived at in Amgen Inc. v. Sanofi, 598 U.S. 594 (2023) supports expanded analysis of whether a claim drawn to an antibody being specific for an epitope, even a specific epitope, permits an applicant to pursue all possible antibodies that are capable of being produced against such an epitope. The disclosure describes that the antibodies were engineered by directed evolution with informatics analysis and computational modeling (see Spec., Examples 2-3). In view of the fact patterns detailed in Amgen v. Sanofi, Applicant is in possession of a handful of engineered antibodies (see Table 8); however, additional antibodies reflective of the broad scope of the claims have not been reduced to practice. Furthermore, the state of the art suggests that single amino acid substitutions may alter antigen-binding specificity of antibodies (see Rudikoff, et al. Proc. Nat. Acad. Sci. USA. Vol. 79 pp. 1979-1983, March 1982; Title, Abstract, Figs. 1-2). However, Applicant has not established that the claimed mutations do not abrogate the antibodies’ ability to bind to HIV gp120. In view of this uncertainty and lack of a sufficient representative number of examples of the claimed genus, the claim is rejected for lack of adequate written description support.
Applicant’s arguments have been fully considered but they are not persuasive:
Applicant presents the following arguments:
The amendments to claim 3 render moot this rejection. Solely to expedite prosecution, and not in acquiescence to the propriety of the rejection, claim 3 has been amended to recite that “the antibody or antigen binding fragment does not comprise each of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 12, 13, 14, 15, 16, and 17, respectively.” A skilled person would understand that an antibody or antibody fragment according to claim 3 can comprise any one, two, three, four, or five of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 12, 13, 14, 15, 16 and 17, respectively, but it cannot comprise all 6 of these sequences. Instant claims 82, 89, 90, 94, and 100 depend from claim 3, directly or indirectly. A skilled person reading the claims in view of the specification would reasonably conclude that the inventors possessed the invention according to instant claims 3, 82, 89, 90, 94, and 100.
Applicant’s arguments are not persuasive because:
Claim 3 encompasses an antibody or antigen binding fragment thereof that comprises a VH with VH CDR1, VH CDR2, and VH CDR3, and a VL that comprises a VL CDR1, VL CDR2, and VL CDR3, and recites several defined sequences for each CDR. Claim 3 also includes a wherein clause on lines 9-12, “wherein the antibody or antigen binding fragment does not comprise each of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 12, 13, 14, 15, 16, and 17, respectively.” As discussed below in the new rejection under 35 U.S.C. §112(b), these limitations are indefinite because it is not clear what “each” means, particularly since the SEQ ID NOs: are not claimed in the alternative. It is not clear if all of the SEQ ID NOs: 12-17 are lacking, or if any one of them are.
(Previous Rejection Maintained) Claims 103 and 106 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 neutralizing HIV-1 virus in vitro, does not reasonably provide enablement for treating HIV infection. 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.
Nature of the invention/Breadth of the claims. The claimed invention is drawn to a method of treating HIV infection, comprising administering to a subject in need a therapeutically sufficient amount of the engineered antibody or antigen binding fragment thereof of capable of binding HIV gp120, wherein the antibody or antigen binding fragment thereof comprises a VH and a VL, wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3, and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1 comprises SEQ ID NO: 12 or 18; the VH CDR2 comprises the sequence of SEQ ID NO: 13, 19, or 61; the VH CDR3 comprises the sequence of 14, 20, 21, 22, 59, 60, 62, 67, or 140-144; the VL CDR1 comprises the sequence of SEQ ID NO: 15, 23, or 63; the VL CDR2 comprises the sequence of SEQ ID NO: 16, 24, or 145; and/or the VL CDR3 comprises the sequence of SEQ ID NO: 17, 25, 68, 146, or 147, wherein the antibody or antigen binding fragment does not comprise each of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 12, 13, 14, 15, 16, and 17, respectively, and wherein the VH and VL comprises the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 10, respectively.
State of the prior art/Predictability of the art. Methods of reducing HIV viral load by administering a therapeutically sufficient amount of an antibody that is broadly neutralizing against HIV-1 (see Caskey. Nature. 2015 Jun 25;522(7557):487-91. doi: 10.1038/nature14411. Epub 2015 Apr 8. Erratum in: Nature. 2016 Jul 28;535(7613):580. doi: 10.1038/nature17642. PMID: 25855300). Caskey also contemplates use of anti-HIV-1 broadly neutralizing antibodies as immunotherapy modalities for HIV-1 prevention, therapy, and cure.
Working examples. The disclosure provides evidence that several of the engineered antibodies exhibit broad and potent neutralization of numerous HIV strains (Example 4). Notably, there are no working examples showing treatment with these engineered antibodies or antigen binding fragments thereof to reducing the likelihood of HIV infection in a subject or treating HIV in a subject.
Amount of experimentation necessary. Due to the prophetic nature of many of the examples provided by the specification (i.e., in vivo treating HIV/AIDS, or reducing the likelihood of HIV infection in a subject not tested for the engineered antibodies), additional experimentation is necessary for one of ordinary skill in the art to figure out how and what the treatment described in the instant application is capable of with regard to treating HIV infection not tested for the engineered antibodies.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Applicant’s arguments have been fully considered but they are not persuasive:
Applicant presents the following arguments:
The amendments to the claims render moot this rejection. Solely to expedite prosecution, and not in acquiescence to the propriety of the rejection, claim 103 has been amended to recite a method of treating HIV by administering to a subject in need thereof a therapeutically sufficient amount of the antibody or antigen binding fragment thereof of claim 76. Claim 106 depends from claim 103 and incorporates all of its elements. As disclosed in the specification, “[i]n certain embodiments, a subject is successfully “treated” for [HIV infection] according to the methods described herein if the patient shows one or more of the following: a reduction in the number of or complete absence of viral load; a reduction in the viral burden; inhibition of or an absence of the virus into peripheral organs; relief of one or more symptoms associated with the disorder, … or any combination thereof.” Specification [0548]. The Examiner has acknowledged that the specification adequately enables the method of reducing HIV-1 viral load according to claim 104. Office Action, page 10. Accordingly, a skilled person considering the claim in view of the specification would reasonably conclude that the specification also adequately enables the method of treating HIV infection according to instant claims 103.
Applicant’s arguments are not persuasive because:
The claims encompass a relatively large group of antibodies for use in treating HIV infection. As discussed in the indefiniteness rejection below, the amendment submitted on 9/3/2025 does not clarify the scope of the claimed invention. The specification does not demonstrate effectiveness in a large number of the claimed antibodies in treating HIV infection. Therefore, this scope of enablement rejection is still appropriate.
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.
(New Rejection Necessitated by Amendment) Claim 3, 4, 18, 60-61, 76, 82, 89-90, 94, 100-104, and 106 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 3 recites the limitation “wherein the antibody or antigen binding fragment does not comprise each of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 12, 13, 14, 15, 16 and 17, respectively.” Claim 3 is indefinite because the metes and bounds of the claim are unclear. It is not clear, from the language of the claim, whether the antibody or antigen binding fragment must comprise none of SEQ ID NOs: 13-17 as CDRs, or if it must merely not comprise at least one of the SEQ ID NOs: 13-17 as a CDR. Claims 4, 18, 60-61, 76, 82, 89-90, 94, 100-104 and 106 depend from claim 3, whether directly or indirectly, and are thus also indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(New Rejection Necessitated by Amendment) Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 is indefinite for the reason described above. If Claim 3 is interpreted to require all 6 of SEQ ID NOs: 13-17 to be lacking from the CDRs, then claim 4, as currently written, does not further limit the scope of the claim. Claim 4 recites those SEQ ID NOs: but does not include a similar wherein clause to that of claim 3. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Subject Matter
Claim 112 is allowable.
SEQ ID NOs: 3-11, 19-20, 23, 24, 55, 59, 60, 62, 63, 65-70, and 112-147 are free of the prior art of record.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671