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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on May 11, 2026. Claims 1 and 4-21 are pending. Claims 9-21 are withdrawn. Claims 1 and 4-8 are currently examined.
Claim Objections
(Previous objection- withdrawn) Claim 1 is objected to because of the following informalities:
Claim 1 recites abbreviation “GRFT” without spelling it out the first time it appears in the claims set. Appropriate correction is required.
This objection is withdrawn in view of the amendment filed on May 11, 2026.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
(Previous rejection-maintained) Claims 1 and 4-8 are rejected under 35 U.S.C. 103 as being unpatentable over O’Keefe et al. (US 8,088,729 B2, patented on Jan. 3, 2012, submitted in IDS filed on 01/06/2023) as evidenced by Steinbach-Rankins et al. (US 2019/0083569 A1, published on Mar. 21, 2019, submitted in IDS filed on 01/06/2023), Moulaei et al. (Structure. 2010 Sep 8;18(9):1104-15) and Ziółkowska et al. (Structure. 2006 Jul;14(7):1127-35).
The base claim 1 is directed to an engineered GRFT polypeptide lacking lysines ("-K GRFT").
O’Keefe teaches an engineered GRFT polypeptide for inhibiting prophylactically or therapeutically a viral infection of a host (See column 4; column 11 lines 43-50). Although O’Keefe does not explicitly teach the engineered GRFT polypeptide lacking lysines ("-K GRFT"), O’Keefe teaches that it is within the skill of the ordinary artisan to select synthetic and naturally-occurring amino acids that effect conservative or neutral substitutions for any particular naturally occurring amino acids. The ordinarily skilled artisan desirably will consider the context in which any particular amino acid substitution is made, in addition to considering the hydrophobicity or polarity of the side-chain, the general size of the side chain and the pK value of side-chains with acidic or basic character under physiological conditions. For example, lysine, arginine, and histidine are often suitably substituted for each other because natural Griffithsin forms dimers, which is critical for the anti-viral function of the polypeptide and mutations that do not modify the electronic or structural environment of the peptide are generated to retain optimal antiviral activity (See column 7, lines 7-67). This can be evidenced by Steinbach-Rankins’s study. Steinbach-Rankins teaches that there are only two lysine residues, Lys6 and Lys99, in the primary sequence of GRFT (i.e. four per GRFT dimer molecule), of which the latter is buried near the interface between two monomers of the domain-swap dimer structure; hence, there may be steric hindrance of two of the four lysine residues within the GRFT protein, resulting in insufficient primary amine groups available for conjugation (paragraph (0107]). Accordingly, one of skilled in the art, at the time of the invention, can implemented an engineered GRFT polypeptide lacking lysine to overcome these challenges. Because the mutation or substitution technique is an ordinary skill in the art, there would be a reasonable expectation of success to make the Lysine substitution to generate a GRFT lacking lysines to improve GRFT conjugation efficiency while ensuring that GRFT antiviral activity is maintained (See [0107]). This can be evidenced by Moulaei’s study. Moulaei et al. teaches that various mutant forms of GRFT including Lys6 (K6) mutation (S65W, S65W/S106E, E119I/S65Y, K6V/S65Y, L2V/S65Y), which kept the dimer-structure and did not form monomers, retained potent anti-HIV activity (See Table 4, page 8), where the Lys6 is substituted by V (Valine). Here it also indicates the suitability for substituting the amino acid lysine because O’Keefe teaches that the ordinarily skilled artisan can generate Griffithsin mutants or variants by, for example, substituting or mutating amino acids which are not critical for the anti-viral function of the polypeptide. Ideally, mutations that do not modify the electronic or structural environment of the peptide are generated to retain optimal antiviral activity. For example, natural Griffithsin forms dimers, which can be advantageous in some embodiments. Therefore, alterations which do not disrupt dimer formation can be preferred. Amino acid residues which are not responsible for folding or stability of the three-dimensional conformation of the Griffithsin polypeptide are candidate residues for mutation (See Column 7, lines 36-55). This can be further evidenced by Ziółkowska’s study. The Figure 1 of Ziółkowska et al. indicates that the Lys6 and Lys99 are both not among the critical structure amino acids based on the structure-based sequence alignment (See page 1128, and Figure 1 and below).
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Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 4-5, O’Keefe teaches that a Griffithsin conjugate comprising a Griffithsin coupled to at least one effector component, which can be the same or different (See column 9, lines 9-38). Although O’Keefe does not teach the nanoparticle conjugation, Steinbach-Rankins teaches that the GRFT is conjugate to EF (electrospun fiber) (see Figs. 4A-4B) and the EF fiber can be comprised of PLGA (See [0053]) and it was discovered that unmodified PLGA EFs completely inhibited HIV penetration for up to 3 days under those administration conditions in vitro (FIG. 9) (See [0099]). It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of O’Keefe, Steinbach-Rankins and Moulaei to arrive at an invention as claimed. One of skill in the art would be motivated to conjugate the CRFT lacking lysine in O’Keefe with the PLGA EF to increase the capability of HIV-infection inhibition. There would be a reasonable expectation of success to develop such an engineered GRFT polypeptide as claimed based on the teachings of Steinbach-Rankins and Moulaei.
Regarding claim 6, O’Keefe teaches that the solid support matrices can be used, such as a matrix comprising a porous surface or membrane, over or through which a sample is flowed or percolated, thereby selectively entrapping or removing infectious virus from the sample (See column 29, lines 1-32), and the functional Griffithsin can be attached onto a solid support matrix (See column 16, lines 15-43).
Regarding claim 7, O’Keefe teaches that the Griffithsin can be covalently coupled to a solid support matrix via an anti Griffithsin antibody, described below. Methods of attaching an antibody to a solid support matrix are well-known in the art (see, for example, Harlow and Lane. Antibodies: A Laboratory Manual, Cold Springs Harbor Laboratory: Cold Spring Harbor, N.Y. (1988)) (See column 27, lines 4-39), where the methods of attaching an antibody to a solid support matrix is the fundamental principle of a lateral flow test.
Regarding claim 8, O’Keefe teaches other types of solid support matrices can be used, such as a matrix comprising a porous surface or membrane, over or through which a sample is flowed or percolated, thereby selectively entrapping or removing infectious virus from the sample (See column 29, lines 10-32), where the porous membrane can be a cellulose or nitrocellulose strip.
Responses to Applicant’s Remarks
Applicant’s arguments filed on May 11, 2026 has been received and fully considered.
Applicant’s amendment regarding the claim objection is considered. The objection is withdrawn.
Applicant’s arguments regarding the claim rejections under 35 U.S.C. § 103 are not found persuasive as follows:
1). Applicant argued that the current rejection does not explain why a skilled artisan would be motivated first to select O'Keefe, Steinback-Rankins, Moulaei and Ziotkowska from all the available griffithsin-related references and second to combine the generic disclosure in O'Keefe (See Remarks, page 6).
Applicant’s argument is not persuasive.
O'Keefe teaches the anti-viral roles of the polypeptide GRIFFITHSIN and discloses a method for isolating and purifying the recombinant Griffithsin (See column 1, lines 15-18; column 11, lines 43-60). O'Keefe also teaches that the ordinarily skilled artisan can generate Griffithsin mutants or variants, where the lysine is one of the amino acids that can be substituted (See column 7). At the same time, Steinbach-Rankins teaches that there are only two lysine residues, Lys6 and Lys99, in the primary sequence of GRFT that can result in insufficient primary amine groups available for conjugation. It was suggested that this may limit efficient conjugation with the fiber carboxyl groups (See Steinbach-Rankins, column 11). Moulaei demonstrates that the Lysine mutation of K6V does not affect anti-HIV activity of GRFT (See Moulaei, Table 4, page 1110). Furthermore, Ziółkowska teaches that the Lys6 and Lys99 are both not among the critical structure amino acids based on the structure-based sequence alignment (See page 1128, and Figure 1 and above). Accordingly, it would be obvious for one of ordinary skill in the art to remove the Lys6, Lys99 or both to overcome the conjugation limitations.
Based on the description above, O'Keefe in view of Steinback-Rankins, Moulaei and Ziotkowska teaches that the instant claims are clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
In addition, such a combination, or a substitution of one element for another
known in the field to have the same function, is evidence that the claimed invention
may be found obvious. See e.g., KSR International v. Teleflex Inc., 82 U.S.P.Q.2d
1385, at 1395. Therefore, the instant invention as a whole was prima facie obvious to
one of ordinary skill in the art at the time the invention was made, as evidenced by the
references, especially in the absence of evidence to the contrary.
2). Applicant argued that the -K GRFT described and claimed in the present application exhibited "enhanced labeling efficiency and high affinity to gp120," without impacting GRFT potency (See Remarks, page 6).
Applicant’s argument is not persuasive.
First, the argued “enhanced” is a relative term having no definite meaning and it is unclear how “enhancing” is determined or what degree of enhancement is necessary in the argument. Applicant has not defined the degree of enhancement (e.g., 2-fold, 5-fold, etc.).
Second, the studies of O'Keefe, Steinback-Rankins, Moulaei and Ziotkowska all teach the anti-viral function of the native GRFT and mutant GRFT for gp120 binding. For example, Moulaei teaches that dGRFT (dimer-GRFT) shows approximately 15-fold greater affinity for gp120 than mGRFT(monomer GRFT), where the mutant forms of GRFT including the K6V (lysine mutation) does not form monomer and all are dimers (See page 1110, right column, paragraphs 1-2; and Table 4).
Also, Steinback-Rankins teaches that two lysine residues, Lys6 and Lys99, in the primary sequence of GRFT (i.e. four per GRFT dimer molecule), of which the latter is buried near the interface between two monomers of the domain-swap dimer structure. Hence, there may be steric hindrance of two of the four lysine residues within the GRFT protein, resulting in insufficient primary amine groups available for conjugation (See [0107[). Because Moulaei and Ziotkowska teaches that the Lys6 and Lys9 can be removed, thus, it is obvious that removing lysine residues can overcome the limitation of efficient conjugation and enhance the labeling efficiency.
Third, the instant claims do not cite limitations for a function at “enhanced labeling efficiency and high affinity to gp120”.
Conclusion
No claims are allowed.
Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/RUIXUE WANG/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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