DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s amendment filed on 10/09/2025 has been entered.
Amended claims 24, 28-29, 33, 37-38 and 40-44 are pending in the present application.
Applicant elected previously the following species:
A: Formula IV;
B: Y1 = Leu, Y2 = Ala, Y3 = Ala, Y4 = not present;
X3 = is a negatively charged;
X4 = Thr;
X5 = is a polar amino acid;
X6 = is a positively charged amino acid;
X7 = is a positively charged amino acid; and
C: AVDTTKR (SEQ ID NO: 59).
The examiner noted previously that Applicant did not elect a specific amino acid for X3, X5, X6 and X7 as required in the Restriction Requirement dated 04/29/2024 (page 3); and instead elected a class of amino acid (also recited in claim 29) for each of X3, X5, X6 and X7. However, in a telephonic interview with Applicant’s representative Shweta Chandra on June 26, 2024, the examiner indicated that since Applicant was also required to elect a specific insert SEQ ID NO. and the elected species must be consistent with the elected species in B (Restriction Requirement dated 04/29/2024, page 4); and with the election of AVDTTKR (SEQ ID NO: 59), Applicant effectively elected previously X3 = Asp, X5 = Thr, X6 = Lys, and X7 = Arg.
In the Amendment dated 10/30/2024, claims 44 and 47 were amended to recite the limitation “AVDTTKF (SEQ ID NO: 59)”; and Applicant stated that F (phenylalanine) is Applicant’s species election for X7 instead of R (arginine).
Claims 33 and 42 were withdrawn previously from further consideration because they are directed to non-elected species
Accordingly, amended claims 24, 28-29, 37-38, 40-41 and 43-44 are examined on the merits herein with the above elected species.
Examiner’s Comment
It is noted that currently amended claims 24 and 28 are broader than previously presented claims 24 and 28, particularly with the new limitation “X3 is a negatively charged amino acid or an uncharged amino acid; or is selected from Glu, Thr, Gly, Asp, or Pro”.
Priority
This application is a CON of U.S. Patent Application No. 16/230,080, filed on 12/21/2018, now US Patent No. 11,236,402; which is a CON of U.S. Patent Application No. 15/244,884, filed on 08/23/2016, now U.S. Patent No. 10,202,657; which is a CON of U.S. Patent Application No. 14/938,154, filed on 11/11/2015, now U.S. Patent No. 9,587,282; which is a CON of U.S. Patent Application No. 14/701,063, filed on 04/30/2015, now U.S. Patent No. 9,458,517; which is a CON of U.S. Patent Application No. 14/444,375, filed on 07/28/2014, now abandoned; which is a CON of U.S. Patent Application No. 14/113,205, filed on 01/22/2014, now U.S. Patent No. 9,193,956; which is a national stage filing under 35 U.S.C. §371 of PCT/US2012/034413, filed on 04/20/2012; which claims the benefit of U.S. Provisional Patent Application No. 61/478,355, filed on 04/22/2011.
Upon reviewing the specifications of the above U.S. Patent Applications and the provisional Patent Application, apart from disclosing 4 specific insertion peptides each with the amino acid sequence of LGETTRP, NETITRP, KAGQANN, or KDPKTTN the provisional Patent Application fails to describe an insertion peptide of Formula I, Formula II, Formula III, or Formula IV as defined in the present application, at least the insertion peptide of Formula IV in claim 29, let alone the elected insertion peptide comprising the amino acid sequence of AVDTTKF. Accordingly, excluding claim embodiments directing to a variant AAV2 capsid protein containing the insertion peptide of LGETTRP, NETITRP, KAGQANN, or KDPKTTN; other claim embodiments under examination have at best the priority date of 04/20/2012, especially the elected insertion peptide of AVDTTKF for a variant AAV2 capsid protein.
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.
Amended claims 24, 28-29, 37-38, 40-41 and 43-44 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:
A variant adeno-associated virus 2 (AAV2) capsid protein comprising a heterologous 10-amino-acid peptide that is inserted in the GH loop between the amino acids 587 and 588 in the AAV2 VP1 sequence of SEQ ID NO: 1, wherein the inserted peptide is: LALGETTRPA (SEQ ID NO: 45), LANETTTRPA (SEQ ID NO: 46), LAKAGQANNA (SEQ ID NO: 47), LAKDPKTTNA (SEQ ID NO: 48), LAKDTDTTRA (SEQ ID NO: 61), LARAGGSVGA (SEQ ID NO: 62), LAAVDTTKFA (SEQ ID NO: 63), or LASTGKVPNA (SEQ ID NO: 64), and wherein the variant AAV2 capsid protein confers increased infectivity to a retinal cell compared to a wild-type AAV2 capsid protein;
does not reasonably provide enablement for other variant AAV capsid proteins as claimed broadly. 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. This is a modified rejection necessitated by Applicant’s amendment.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
The instant specification is not enabled for a variant adeno-associated virus (AAV) capsid protein as claimed broadly for the reasons discussed below.
1. The breadth of the claims
Amended claims 24, 28-29, 37-38, 40-41 and 43-44 encompass a variant AAV-2 capsid protein comprising an insertion of from about 5 amino acids to about 11 amino acids, wherein the amino acid insertion is in the GH loop between amino acids 587 and 588 relative to SEQ ID NO: 1 (the amino acid sequence of AAV2 VP1 capsid protein), wherein the insertion peptide is a peptide of Formula IV as defined in currently amended independent claim 24, wherein the variant AAV capsid protein confers increased infectivity of a retinal cell (e.g., retinal ganglion cells, amacrine cells, horizontal cells, bipolar cells, photoreceptor cells, Muller glial cells and retinal pigmented epithelial cells) compared to a corresponding parental AAV capsid protein and is not SEQ ID NO: 13 (LGETTRP); with the inserted peptide of Formula IV is defined as Y1Y2X1X2X3X4X5X6X7Y3Y4, wherein:
each of Y1-Y4, if present, is independently selected from Ala, Leu, Gly, Ser and Thr (5 choices maximum);
X1, if present, is a positively charged amino acid or an uncharged amino acid (15 choices maximum), or is selected from Leu, Asn, Arg, Ala, Ser, and Lys;
X2 is a negatively charged amino acid or an uncharged amino acid (15 choices maximum), or is selected from Gly, Glu, Ala, Val, Thr, and Asp;
X3 is a negatively charged amino acid or an uncharged amino acid (15 choices maximum); or is selected from Glu, Thr, Gly, Asp, or Pro;
X4 is selected from Thr, Ile, Gly, Lys, Asp, and Gln (6 choices maximum);
X5 is a polar amino acid (11 choices maximum), an amino acid having a free hydroxyl group, a hydrophobic amino acid, or is selected from Thr, Ser, Val, and Ala;
X6 is a positively charged amino acid or an uncharged amino acid (15 choices maximum), or is selected from Arg, Val, Lys, Pro, Thr, and Asn; and
X7, if present, is a positively charged amino acid or an uncharged amino acid (15 choices maximum), or is selected from Pro, Gly, Phe, Asn, and Arg.
Thus, these claims encompass at least a variant AAV-2 capsid protein comprising an amino acid insertion of from about 5 amino acids to about 11 amino acids in the GH loop between amino acids 587 and 588 relative to SEQ ID NO: 1, wherein the inserted peptide is a peptide of Formula IV containing of up to about 3 x 1010 (54 x 15 x 15 x 15 x 6 x 11 x 15 x 15) different amino acid sequences for an 11-amino-acid inserted peptide in claim 24 or claim 28, or up to about 3.9 x 107 (24 x 15 x 15 x 15 x 6 x 4 x 6 x 5) different amino acid sequences for an 11-amino-acid insertion peptide in claim 29; including the elected amino acid insert of AVDTTKF (SEQ ID NO: 59) and wherein the variant AAV capsid protein confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein and is not SEQ ID NO: 13.
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (04/20/2012), little was known about the nature of a 5-11 amino-acid insertion peptide in the GH loop or loop IV of a native AAV capsid protein that confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein as evidenced at least by the teachings of Douar et al (Virology 309:203-208, 2003), Buning et al (Gene Therapy 10:1142-1151, 2003; IDS), White et al (Human Gene Therapy 19:1407-1414, 2008; IDS) and Rabinowitz et al (US 2006/0188483). Douar et al reported deleterious effect of a 13-amino-acid peptide containing the SV40 large T antigen NLS of PKKKRKV being inserted at amino acid 587 of the AAV2 capsid; and stated “Altogether, these results indicate that the nature of the peptide inserted at position 587 in the capsid may have important consequences on both particle formation and infectivity” (Abstract), and “Because of the high level of basic residue in the NLS sequence, we had expected that the peptide would not alter too profoundly the binding of the particles to the cell-surface HSPGs. However, it appears that the integrity of the region surround position 587 is required for optimal infectivity of the particles through binding to their cellular receptor” (page 206, right column, last two sentences in first full paragraph). Buning et al also reported that not every ligand, even if comparable in length is tolerated at a specific insertion site; and stated “Shi et al73 inserted either the BPV or the LH ligand both flanked by the GLS scaffold sequences at site 459 and observed that the BPV ligand (a six-amino-acid insertion) generated fully infectious particles, whereas the insertion of the 10 amino-acid LH peptide created noninfectious virus particles. Our laboratory made a similar observation when trying to insert multimers of the L14 sequence at position 587: larger insertions at position 587 resulted in a decrease of the packaging efficiency although the insertion of a 34 amino acid containing the Z34C protein A domain of Staphylococcus aureus (see below) was well tolerated. These results show that the maximal length of the peptide tolerated at this position depends on the sequence itself. The precise determinants of this phenomenon are unknown” (page 1148, right column, last paragraph continues to first paragraph on right column). Moreover, White et al constructed 6 independent mutant AAVs containing peptide ligands that have been identified by in vitro phage display with high affinity binding for known and unknown receptors on human airway epithelial cells, but surprisingly only one of the 6 different capsid mutants, with the peptide sequence THALWHT, showed the highest transduction in undifferentiated human airway epithelial cells and polarized cells (see at least Abstract; page 1410, right column, third paragraph; and Figs. 1B). Additionally, Wu et al (J. Virology 80:11393-11397, 2006; IDS) demonstrated that single amino acid changes in an AAV capsid protein can influence titer, heparin binding and tissue tropism in different adeno-associated virus serotypes (see at least the Abstract).
Furthermore, please note that the physiological art is recognized as unpredictable (MPEP 2164.03).
3. The amount of direction or guidance provided
Apart from disclosing that following a process of directed evolution created photoreceptor-permissive AAV variants through the application of positive selection and induced mutagenesis, the cap genes of 50 variants were sequenced to determine the most prominent and successful variants to have permissive mutations for intravitreal photoreceptor transduction, and remarkably nearly 2/3 of clones contained the same 7-mer motif LGETTRP (SEQ ID NO: 13); with the next most prominent variant NETITRP and 6 other less frequent variants listing in decreasing order KAGQANN, KDPKTTN, KDTDTTR, RAGGSVG, AVDTTKF (elected insertion peptide) and STGKVPN, wherein each of the above 7-mer motifs was flanked by the spacer LA amino acids at the N-terminus and an A at the C-terminus, and each peptide is inserted into the wild type AAV2 genome between amino acid 587 and 588 (see at least example 1, particularly paragraphs [00206]-[00214]; and Tables 1-2); the instant specification fails to provide sufficient guidance for an ordinary skilled artisan on how to make and use any other insertion peptide of Formula IV containing up to about 3 x 1010 or 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide as encompassed by claims 24 and 29, respectively; and such insertion peptide also confers the variant AAV2 capsid protein an increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein. Apart from the spacers LA amino acids at the N-terminus and an A at the C-terminus, there is no apparent common core amino acid sequence that is shared in all of the above disclosed 8 insertion peptides. It is noted that AVDTTKF is the only insertion peptide among up to 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide encompassed by claim 29, that meets both the recited Formula IV requirements and possesses the recited property of conferring increased infectivity of a retinal cell compared to a corresponding parental AAV-2 capsid protein. The mere disclosure of this single insertion peptide of AVDTTKF is hardly a representative number of species for a genus of an insertion peptide of Formula IV containing up to about 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide with the desired property as encompassed by claim 29. Nor does the disclosure of the above 8 insertion peptides hardly a representative number of species for a genus of an insertion peptide of Formula IV containing up to about 3 x 1010 different amino acid sequences for an 11-amino-acid insertion peptide with the desired property as encompassed by claim 24. It is undue experimentation for an ordinary skill in the art to screen and determine at least each of 3 x 1010 or 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide as encompassed in claims 24 and 29, respectively; on whether it possesses the desired property, particularly the unpredictability of which particular or specific insertion peptide would or would not possess the ability of conferring increased infectivity of a retinal cell compared to a corresponding parental AAV-2 capsid protein.
As already noted above, Douar et al taught that the nature of the peptide inserted at position 587 in the AAV2 capsid may have important consequences on both particle formation and infectivity; and Buning et al also reported that not every ligand, even if comparable in length is tolerated at a specific insertion site and this tolerance depends on the sequence itself, and the precise determinants of this phenomenon are unknown. There is no evidence of record indicating or suggesting any 5-mer or 6-mer of the disclosed AVDTTKF insertion peptides still retain the ability to confer a variant AAV-2 capsid protein an increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein, let alone truncated versions of a plethora of other insertion peptides of Formula IV encompassed by the instant claims. Particularly, Wu et al already demonstrated that single amino acid changes in an AAV capsid protein can influence titer, heparin binding and tissue tropism in different adeno-associated virus serotypes. It is also not entirely clear whether the insertion peptide (e.g., LGETTRP, AVDTTKF and STGKVPN) exerts the effect on an increased infectivity of a retinal cell for the variant AAV2 capsid protein on its own or does it also require its spacer amino acids and/or surrounding amino-acid environment, such as the region surround the insertion site between amino acids 587 and 588 relative to SEQ ID NO: 1? There is no evidence of record indicating that the insertion peptide AVDTTKF without the flanking spacer LA amino acids at the N-terminus and an A at the C-terminus still mediates an increased infectivity of a retinal cell for the variant AAV2 capsid protein. Even several years after the effective filing date of the present application (04/20/2012), Khabou et al (Biotechnology and Bioengineering 113:2712-2724, 2016) demonstrated that unlike AAV2-7m8 having a capsid-displayed peptide insertion of 10 amino acids LALGETTRPA with enhanced retinal transduction properties, the 7m8 insertion peptide has no positive effect on the retinal transduction properties of AAV5 or AAV8 tested after intravitreal injection (see Abstract; section titled “Retinal transduction efficiency of AAV2, 5, 8 and 9, compared to their 7m8 insertion variants” on pages 2716-1717; Figure 3). Additionally, Khabou et al still used the spacer LA amino acids at the N-terminus and an A at the C-terminus of the 7-mer insertion peptide.
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the above issues, it is incumbent upon the present application to do so. Given the state of the prior art discussed above, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use a variant AAV-2 capsid protein that confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein as claimed broadly by the present application.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issue set forth above, the state and unpredictability of the relevant art and especially for attaining the desired property of increased infectivity of a retinal cell mediated by a variant AAV2-capsid protein in comparison to a corresponding parental AAV capsid protein, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
Response to Arguments
I. Applicant’s arguments related to the above modified 112 (pre-AIA ) first paragraph rejection in the previous Amendment filed on 04/14/2025 (pages 9-12) and Examiner’s Responses are restated below.
A. Applicant argued previously that it would be well within the skill of the ordinary artisan to make and use the claimed invention at the time of the invention as described in Example 1 to identify variants; and that simply the claims may be broad does not establish a lack of enablement even the number of capsids falling within Formula IV in claim 24 not all will fulfill the additional requirement that they possess the ability to confer increased infectivity to a retinal cell compared to a wild type AAV2 capsid protein.
The main issue is not simply generating a large library and screening for desired variants. Rather it is the unpredictability to attain of a variant AAV2 capsid protein comprising an insertion peptide of from about 5 amino acids to about 11 amino acids of Formula IV, wherein the insertion peptide is in the GH loop between amino acids 587 and 588 relative to SEQ ID NO: 1 and wherein the variant AVV2 capsid protein confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein. The mere disclosure of a single insertion peptide of AVDTTKF is hardly a representative number of species for a genus of an insertion peptide of Formula IV containing up to about 3 x 1010 or 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide with the desired property as encompassed by claims 24 and 29, respectively. Indeed, it is undue experimentation for an ordinary skill in the art to screen and determine at least each of 3 x 1010 or 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide as encompassed in claims 24 and 29, respectively; on whether it possesses the desired property, particularly the unpredictability of which particular or specific insertion peptide would or would not possess the ability of conferring increased infectivity of a retinal cell compared to a corresponding parental AAV-2 capsid protein. Moreover, it is also not entirely clear whether the insertion peptide (e.g., LGETTRP, AVDTTKF and STGKVPN) exerts the effect on an increased infectivity of a retinal cell for the variant AAV2 capsid protein on its own or does it also require its spacer amino acids and/or surrounding amino-acid environment, such as the region surround the insertion site between amino acids 587 and 588 relative to SEQ ID NO: 1? There is no evidence of record indicating that the insertion peptide AVDTTKF without the flanking spacer LA amino acids at the N-terminus and an A at the C-terminus still mediates an increased infectivity of a retinal cell for the variant AAV2 capsid protein. Please see the above modified 35 U.S.C. 112 (pre-AIA ), first paragraph rejection for details.
B. With respect to the issue of unpredictability, Applicant argued previously that Douar is directed to a 13-amino-acid peptide which is not covered by the instant claims; while the shortest insert tested in Bunning was 14 amino acids, not the shorter inserts of 5-11 amino acids as currently claimed. Applicant also argued that White investigated AAVs in human airway epithelial cells, not in retinal cells as claimed; and it is well recognized that the airway epithelial cells are not retinal cells and that AAVs bind differently between the two cell types. Applicant also argued that the Examiner provides no direction to what Rabinowitz teaches that provides a basis for unpredictability. Applicant further argued that Wu investigates differences in AAV1 and AAV6 (99.2% sequence homology) to identify amino acid residues responsible for their heparin binding and liver tropism, and the single amino acid changes referenced by the Examiner is in closely related AAV serotypes; but this degree of sequence homology is not shared with AAV2 (AAV1 and AAV6 are each approximately 83% homologous to AAV2).
First, both Douar and Bunning indicate and suggest at least that the nature and/or the sequence of the peptide inserted at position 587 in the AAV2 capsid protein may have important consequences on both particle formation and infectivity. Buning et al also reported that not every ligand, even if comparable in length is tolerated at a specific insertion site; and stated “Shi et al73 inserted either the BPV or the LH ligand both flanked by the GLS scaffold sequences at site 459 and observed that the BPV ligand (a six-amino-acid insertion) generated fully infectious particles, whereas the insertion of the 10 amino-acid LH peptide created noninfectious virus particles…. These results show that the maximal length of the peptide tolerated at this position depends on the sequence itself. The precise determinants of this phenomenon are unknown” (page 1148, left column, last paragraph continues to first paragraph on right column).
Second, White et al constructed 6 independent mutant AAVs containing peptide ligands that have been identified by in vitro phage display with high affinity binding for known and unknown receptors on human airway epithelial cells, but surprisingly only one of the 6 different capsid mutants, with the peptide sequence THALWHT, showed the highest transduction in undifferentiated human airway epithelial cells and polarized cells. White’s results indicate or suggest at least the unpredictability for attaining a desired infectivity for mutant/variant AAVs in targeted human airway epithelial cells and polarized cells, which would similarly extend to other target cells such as retinal cells.
Third, Rabinowitz was cited simply to indicate the state of the prior art, particularly regarding to a 5-11 amino-acid insertion peptide in the GH loop or loop IV of a native AAV capsid protein that confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein.
Fourth, although Wu investigates differences in AAV1 and AAV6 (99.2% sequence homology) to identify amino acid residues responsible for their heparin binding and liver tropism, Wu’s results still indicate and suggest significant impact of single amino acid changes in an AAV capsid protein on titer, heparin binding and tissue tropism. This would similarly apply to a broad genus of amino acid changes/substitutions/modifications among the about 3 x 1010 or 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide as encompassed by claims 24 and 29, respectively; and such insertion peptide also confers the variant AAV2 capsid protein an increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein.
C. Applicant argued previously that the currently pending claims cover a large number of capsid variants; but it was well within the skilled artisan’s ability to make, screen and use variants derived from this large library. In fact, many of the references (e.g., US 17/842,530, US 18/447,866 and US 11,565,000) cited by the Examiner use the same methods to generate and screen their variant capsid libraries. Thus, Applicant provided sufficient support that the skilled artisan could make and appropriately screen the variant capsids not only at the date of filing but that continue to find use in art. Applicant further argued that experimentation may be complex does not necessarily make it undue, if the art engages in such experimentation. In this instance, Applicant submitted that by teaching how to make variant AAV2 capsid and screen for the desired property (e.g., enhanced retinal infectivity), more than sufficient teaching is provided as to how to make and use the present invention, as stated in MPEP at 2164.01(b).
First, once again the main issue is not simply generating a large library and screening for desired variants. Rather it is the unpredictability to attain of a variant AAV2 capsid protein comprising an insertion peptide of from about 5 amino acids to about 11 amino acids of Formula IV, wherein the insertion peptide is in the GH loop between amino acids 587 and 588 relative to SEQ ID NO: 1 and wherein the variant AVV2 capsid protein confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein.
Second, each of US 17/842,530, US 18/447,866 and US 11,565,000 has a post-filing date of the present application; and their specific disclosures do not reflect the state of the prior art at the effective filing date of the present application.
Third, it is noted that MPEP stating at 2164.01(b): “As long as the specification discloses at least one method for making and using the claimed invention that bears reasonable correlation to the entire scope of the claim, then the enablement requirement of 35 U.S.C. 112 is satisfied”. Please refer to the above modified 35 U.S.C. 112 (pre-AIA ), first paragraph rejection for details. Additionally, as set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
II. Applicant’s response in the Amendment filed on 10/09/2025 (pages 8-12) has been fully considered, but it is respectfully not found persuasive for the reasons discussed below.
Applicant argued that the relative skill in the art is high, specifically a person having a Ph.D. degree in molecular biology, AAV biology and protein engineering, as well as extensive knowledge of research and treatment of eye and its retinal disease. Applicant also argued that while the claims potentially cover a large number of capsid proteins (e.g., 3 x 1010), however, simply covering a large number of capsid proteins does not render the claims unpatentable; and the claimed subject matter is limited to a subset of these capsids, specifically those that confer increased infectivity of a retinal cell relative to a parental capsid protein. Applicant also argued that even in unpredictable arts, a disclosure of every operable species is not required. Instead, the specification is replete with specific guidance on how to perform the subject matter of claims, including Example 1 provides guidance for making a diverse 7-mer display library by cloning dsDNA inserts into a specific restriction site, and packaging or encapsulating the variant genome within the capsid protein variant that that genome encoded; and directed evolution method steps have also been described. Applicant noted that it is not surprising that only a few variants were detected, however, that number was sufficient for Applicant to understand and recognize that the variants fall within a recognized group such as Formula IV based on a single experiment disclosed in the application. It is that recognition of inserts of Formula IV demonstrating increased infectivity of retinal cells that the Applicant is currently claiming, not simply the inserts of Formula IV. Applicant further argued that the methods provided in the application were continued to be used by the laboratory’s personnel after the filing date and provided for additional inserts within Formula IV that provided increased infectivity of a retinal cell. As an example, Timothy Day’s dissertation includes many inserts such as the inserts in the Supplementary Table 2 that are encompassed by Formula IV and possess increased infectivity of a retinal cell in canines. Additionally, the Supplementary Table 2 also provides guidance on the linkers, and linkers may impact the 7-mer insert but it is easily determined by the skilled artisan if the insert is within Formula IV and if it increases infectivity of a retinal cell. Applicant also argued that the experimentation may be complex does not necessarily make it undue, if the art typically engages in such experimentation and the methods used in the present application were routine. Finally, Applicant argued that the guidance in the specification significantly decreases the unpredictability asserted by the examiner’s reliance upon at least the teachings of Douar et al, Buning et al, White et and Rabinowitz et al; and it is the Applicant’s discovery/realization that peptides of a specific motif such as Formula IV, inserted in the GH loop between amino acids 587 and 588 in an AAV capsid relative to SEQ ID NO: 1 are more likely to affect the capsid in the desired manner such as increased infectivity of retinal cells than random inserts.
First, the determination of an enabling disclosure under 35 U.S.C. 112 (pre-AIA ) does not require an ordinary skill in the art to be a person having a Ph.D. degree in molecular biology, AAV biology and protein engineering, as well as extensive knowledge of research and treatment of eye and its retinal disease.
Second, the claims encompass all variant AAV2 capsid proteins that confer increased infectivity of a retinal cell compared to a corresponding parental AAV2 capsid protein, as long as they comprise a peptide insertion of from about 5 amino acids to about 11 amino acids that is in the GH loop between amino acids 587 and 588 relative to SEQ ID NO: 1, and the inserted peptide is of Formula IV; and not a subset of variant AAV2 capsid proteins. Even assuming that Applicant intends to claim a subset of variant AAV2 capsid proteins recited in any one of claims 24 and 28-29, which specific structural features/primary amino acid sequences that all members of this subset of variant AAV2 capsid proteins possess that have the recited property of conferring increased infectivity of a retinal cell compared to a corresponding parental capsid protein and is not SEQ ID NO: 13 vs other variant AAV2 capsids also containing an inserted peptide of Formula IV that do not possess the recited property at the effective filing date of the present application and not at any future date? Please refer to the Wands factor analysis in the above modified 35 U.S.C. 112 rejection for details.
Third, the above Office Action does not require a disclosure of every operable species. Apart from the spacers LA amino acids at the N-terminus and an A at the C-terminus, there is no apparent common core amino acid sequence that is shared among the 8 insertion peptides disclosed in Example 1 of the present application. It is noted that AVDTTKF is the only insertion peptide among up to 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide encompassed by claim 29, that meets both the recited Formula IV requirements and possesses the recited property of conferring increased infectivity of a retinal cell compared to a corresponding parental AAV-2 capsid protein. The mere disclosure of this single insertion peptide of AVDTTKF is hardly a representative number of species for a genus of an insertion peptide of Formula IV containing up to about 3.9 x 107 different amino acid sequences for an 11-amino-acid insertion peptide with the desired property as encompassed by claim 29. Nor does the disclosure of the 8 insertion peptides hardly a representative number of species for a genus of an insertion peptide of Formula IV containing up to about 3 x 1010 different amino acid sequences for an 11-amino-acid insertion peptide with the desired property as encompassed by claim 24.
Fourth, the additional inserts with specific primary amino acid sequences that are provided in the Supplementary Table 2 are results obtained from further experimentation and/or additional screening after the effective filing date of the present application; and they were not specifically disclosed in the present application. Applicant also noted that the Supplementary Table 2 provides guidance on the linker, and linkers may impact the 7-mer insert; which are essential guidance that should have been provided in the as-filed specification. The Supplementary Table 2 also does not provide any peptide insert shorter than 10 amino acids, including an insert peptide of about 5 amino acids, that is of Formula IV and confers increased infectivity of a retinal cell as encompassed by the instant claims.
Fifth, the guidance provided in the as-filed specification does not decrease the unpredictability as set forth in the above 112 rejection, particularly in light of the teachings of Douar et al, Buning et al and White et al at the effective filing date of the present application. Once again, please refer to the Wands factor analysis in the above modified 35 U.S.C. 112 rejection for details.
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.
Amended claims 24 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,565,001 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because a rAAV virion comprising: a) a variant AAV capsid protein comprising an insertion of a heterologous peptide having a length of from 10 amino acids to 20 amino acids in the capsid protein GH loop (e.g., the insertion site is located between amino acids corresponding to amino acids 587 and 588 of VP1 of AAV2, or the corresponding position in the capsid protein of another AAV serotype; see dependent claim 3) relative to a corresponding parental AAV capsid protein, wherein the heterologous peptide comprises the amino acid sequence LAKSDQSKPA (SEQ ID NO:61), and wherein the variant capsid protein confers increased infectivity of a retinal cell compared to the infectivity of the retinal cell by a control AAV virion comprising the corresponding parental AAV capsid protein; and b) a heterologous nucleic acid comprising a nucleotide sequence encoding a heterologous gene product, in claims 1-7 of U.S. Patent No. 11,565,001 anticipates a variant AAV capsid protein in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. Please note LAKSDQSKPA corresponds to the sequence Y1Y2X1X2X3X4X5X6X7Y3; and X3 is Asp (D).
Amended claims 24, 28-29, 37-38, 40-41 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 6-17 of U.S. Patent No. 11,939,355.
Although the claims at issue are not identical, they are not patentably distinct from each other because an AAV2 VP1 capsid protein comprising an amino acid sequence comprising sequence LAxxDxTKxA (SEQ ID NO: 106), wherein the amino acid sequence is inserted between amino acids N587 and R588 of the AAV2 VP1 capsid protein and wherein the AAV2 VP1 capsid protein comprises an N382D and an V708I amino acid substitution, numbered relative of SEQ ID NO:110 in claims 4 and 6-17 of US 11,939,335 anticipates or encompasses a variant AAV capsid protein in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. Please note SEQ ID NO: 106 corresponds to the sequence Y1Y2X1X2X3X4X5X6X7Y3, wherein each of X1, X2, X4 and X7 in SEQ ID NO: 106 is independently selected from any amino acid that encompasses the amino acids at the corresponding positions in the insertion peptide of the present application; and such variant AAV capsid also confers increased infectivity of a retinal cell compared to a corresponding parental AAV capsid protein.
Amended claims 24 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,236,402.
Although the claims at issue are not identical, they are not patentably distinct from each other because a rAAV2 virion comprising: a) a variant AAV capsid protein comprising a peptide insertion relative to a corresponding parental AAV capsid protein as set forth in SEQ ID NO: 1, wherein the peptide insertion is between amino acids 587 and 588 relative to SEQ ID NO: 1, and wherein the peptide insertion comprises the amino acid LALGETTRPA (SEQ ID NO: 45); and b) a heterologous nucleic acid comprising a nucleotide sequence encoding an anti-angiogenic polypeptide, in claims 1-8 of US Patent No. 11,236,402 anticipates a variant AAV capsid protein in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. Please note LALGETTRPA corresponds to the sequence Y1Y2X1X2X3X4X5X6X7Y3.
Amended claims 24 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 25-28 of U.S. Patent No. 10,202,657 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because a rAAV virion comprising: a) a variant AAV capsid protein comprising a peptide insertion relative to a corresponding parental AAV capsid protein, wherein the peptide insertion is located between two adjacent amino acids at a position between amino acids corresponding to amino acids 570 and 611 of VP1 of AAV2 or the corresponding position in the capsid protein of another AAV serotype, including the insertion site is located between amino acids corresponding to amino acids 587 and 588 of VP1 of AAV2 or the corresponding position in the capsid protein of another AAV serotype (see claims 3 and 27), and wherein the peptide insertion comprises an amino acid sequence selected from the group consisting of NETITRP (SEQ ID NO: 14), KAGQANN (SEQ ID NO: 15), and KDPKTTN (SEQ ID NO: 16); and b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product, in claims 1-10 and 25-28 of US Patent No. 10,202,657 anticipates a variant AAV capsid protein in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. Please note each of NETITRP, KAGQANN and KDPKTTN corresponds to the sequence X1X2X3X4X5X6X7.
Amended claims 24 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,554,180 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because a rAAV virion comprising: a) a variant AAV capsid protein comprising a heterologous peptide insertion in the capsid protein GH loop (e.g., the insertion site is located between amino acids corresponding to amino acids 587 and 588 of VP1 of AAV2, or the corresponding position in the capsid protein of another AAV serotype; see dependent claim 3) relative to a corresponding parental AAV capsid protein, wherein the heterologous peptide comprises the amino acid sequence LAPDSTTRSA (SEQ ID NO:53), and wherein the variant capsid protein confers increased infectivity of a retinal cell compared to the infectivity of the retinal cell by a control AAV virion comprising the corresponding parental AAV capsid protein; and b) a heterologous nucleic acid comprising a nucleotide sequence encoding a heterologous gene product, in claims 1-7 of U.S. Patent No. 11,554,180 anticipates a variant AAV capsid protein in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. Please note LAPDSTTRSA corresponds to the sequence Y1Y2X1X2X3X4X5X6X7Y3.
Amended claims 24 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,565,000 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because a rAAV virion comprising: a) a variant AAV capsid protein comprising an insertion of a heterologous peptide having a length of from 10 amino acids to 20 amino acids in the capsid protein GH loop (e.g., the insertion site is located between amino acids corresponding to amino acids 587 and 588 of VP1 of AAV2, or the corresponding position in the capsid protein of another AAV serotype; see dependent claim 3) relative to a corresponding parental AAV capsid protein, wherein the heterologous peptide comprises the amino acid sequence LATTSQNKPA (SEQ ID NO:50), and wherein the variant capsid protein confers increased infectivity of a retinal cell compared to the infectivity of the retinal cell by a control AAV virion comprising the corresponding parental AAV capsid protein; and b) a heterologous nucleic acid comprising a nucleotide sequence encoding a heterologous gene product, in claims 1-7 of U.S. Patent No. 11,565,000 anticipates a variant AAV capsid protein in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. Please note LATTSQNKPA corresponds to the sequence Y1Y2X1X2X3X4X5X6X7Y3.
Amended claims 24 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5 and 7-16 of US Patent No. 12,310,997.
Although the claims at issue are not identical, they are not patentably distinct from each other because a variant AAV capsid comprising a heterologous peptide covalently inserted in the GH loop of the capsid protein relative to a corresponding parental AAV capsid protein (e.g., the insertion site is located between amino acids corresponding to amino acids 587 and 588 of the VP1 of AAV2, wherein the in