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 .
Application Status
This action is written in response to applicant’s correspondence received 01/17/2025. Claims 33-54 are currently pending. Claims 38-39, 41, and 49-54 are withdrawn from prosecution as being drawn to non-elected subject matter. Claims 34 and 45 are cancelled. Accordingly, claims 33, 35-37, 40, 42-44 and 46-48 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Maintained - Claim Rejections - 35 USC § 112 – Improper Markush Grouping
Claims 33, 42 and 43 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 groupings of claims 33, 42 and 43 are 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:
The claims are drawn to polynucleotide and polypeptide sequences. Claim 34 recites the polynucleotide encoding a first polypeptide part comprising an amino acid sequence of the general formula of SEQ ID NO: 12, wherein X is any proteinogenic or non-proteinogenic amino acid residue; and further comprising a second polypeptide part comprising a general formula of SEQ ID NO: 11, wherein each “Z” position is one of 2 to 6 amino acids. It is noted that, in the species election received 03/20/2024, Applicant elected the polypeptide sequence of SEQ ID NO: 6, which is encompassed by claims 33, 42 and 43. However, the other possible embodiments of said claims represent a variety of sequences such that none of the possible embodiments share a common sequence. Because the sequences do not share a common sequence, they do not share a substantial structural feature or a common use that flows from a substantial structural feature.
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.
Response to Arguments
Applicant's arguments filed 01/17/2025 have been fully considered but they are not persuasive.
Applicant argues that the first polypeptide part is proper because the alternatives are all members of the same art-recognized class, namely leucine zippers, and as such, each member of the group shares a common use that flows from that common structural feature (i.e., the heptad repeat with a leucine every seventh residue). However, please note that the claims do not require a leucine zipper. Instead, due to the ’X’ residues, which may be any proteinogenic or non-proteinogenic amino acid residues, they embrace amino acid sequences that would not reasonably be expected to form leucine zippers, such as sequences that do not form alpha helices that participate in coiled-coil formation. For example, proline and glycine are both known “helix breakers”, which are residues with a high propensity to destabilize alpha helices (Neil & DeGrado. “A Thermodynamic Scale for the Heli-Forming Tendencies of the Commonly Occurring Amino Acids”. Science. 1990 Nov 2;250(4981):646-51.; see attached PTO-892). Similarly, if a leucine zipper is defined by a repeat of seven amino acids (a-g), then generally residues ‘a’ and ‘d’ are hydrophobic and form a hydrophobic interaction at the dimer interface, as disclosed by Zeng (p. 3673, right; Zeng et al. “Buried asparagines determine the dimerization specificities of leucine zipper mutants.” Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3673-8.; see attached PTO-892). The instant claims require only one of these positions to be hydrophobic, and allow the other one to be hydrophilic. If these hydrophilic ‘d’ residues cannot form a stable interaction with the opposite strand of the dimer, then this would reasonably be expected to disrupt leucine zipper formation. Therefore, the claims encompass a broader array of possible structures than leucine zippers.
Applicant also argues that the second polypeptide part of the Markush grouping is proper because the alternatives are all members of the same art-recognized class and have a common use as disclosed in the specification. This argument is not persuasive because, although the evidence provided from Example 6 indicates that sequences following the motif in which Z1 and Z2 are present appear to tolerate substitutions and belong to the same art-recognized class of PDZ-binding domains, the claims more broadly encompass structures wherein Z1 and Z2 are absent, and it is unclear whether removal of those residues would yield a structure belonging to the same class, with a common use which flows from the remaining shared structure.
Modified - 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 33, 40, 42-44 and 46-48 are rejected under 35 U.S.C. 103 as being unpatentable over Bach et al. (of record) in view of Weinberg (of record), Chen, U.S. Patent Publication No. 20090305946 A1 (of record, herein PGPUB946), Dev (of record), Alfonso (of record) and Erlendsson (of record).
Bach teaches a dimeric polypeptide comprising a second polypeptide part comprising or consisting of an amino acid sequence selected from the group consisting of Class I PDZ domain binding motifs (PBM), Class II PBM and Class III PBM wherein the second polypeptide binds to a PDZ domain (relevant to claim 45) and the polypeptide has a Ki for the PDZ domain below 25 μM (relevant to claim 47):
Here we report the design and synthesis of a novel dimeric inhibitor, Tat- NPEG4(IETDV)2 (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 [abstract]
by linking two pentapeptides (IETAV) with a monodisperse polyethylene glycol (PEG) linker of optimal length (PEG4), a high-affinity dimeric ligand, PEG4(IETAV)2 (O-dimer) (Fig. 1B), was obtained with Kd of 10 nM towards tandem PDZ1-2 of PSD-95
Bach further teaches that the dimeric polypeptide binds the PDZ domains of PSD-95 and thereby inhibits the interaction between PSD-95 and its targets, including NMDA receptors (relevant to claim 46; see Fig. 1 and below):
The postsynaptic scaffolding protein PSD-95 simultaneously binds the N-methyl-D - aspartate (NMDA)-type of ionotropic glutamate receptors and the enzyme neuronal nitric oxidesynthase (nNOS) through its PDZ1 and PDZ2 domains…Ligands that bind to the first two PDZ domains of PSD-95 inhibit the formation of the ternary nNOS/PSD- 95/NMDA receptor complex
Bach further teaches that “the dimeric polypeptide is a highly effective neuroprotective agent with therapeutic potential in stroke” (see abstract).
Bach teaches linking two pentapeptides with a PEG linker to create a high-affinity dimeric ligand (p. 3317).
Bach does not teach:
A first polypeptide part comprising or consisting of an amino acid sequence of the general formula (I): L-[X]6-L[X]6- L[X]6-L capable of forming a homodimer with an identical first polypeptide part (relevant to claim 33 in part)
A polynucleotide comprising a sequence encoding upon expression the polypeptide (relevant to claim 33 in part)
The polynucleotide further comprising a promoter sequence (relevant to claim 48)
The polynucleotide further comprising a linker wherein the linker is a glycine serine linker selected from the group consisting of GGGGS (glinker4), GGS (gLinker2), GGGS (gLinker3), GGGGSG (gLinker5), GGGGSGG (gLinker6) (relevant to claim 44)
That the first polypeptide parts form a homodimer while the second polypeptide parts comprise the PBM (relevant to claim 33 in part).
PGPUB946 teaches the use of leucine zipper motifs in polypeptide oligomers to promote oligomerization of polypeptides in which they are found:
[0086] Another method for preparing the oligomers of the disclosure involves use of a leucine zipper. Leucine zipper domains are peptides that promote oligomerization of the polypeptides in which they are found.
PGPUB946 further teaches that the oligomers, including the leucine zipper motifs, can be encoded as polynucleotides in expression vectors:
[0020] The disclosure also provides an isolated polynucleotide consisting essentially of a nucleotide sequence encoding a peptide or oligomer described herein. The polynucleotide can be incorporated in to an expression vector.
Therefore, PGPUB946 teaches that leucine zipper motifs, such as that described in amended claim 1, promote oligomerization of polypeptides and can be encoded as polynucleotides.
Weinberg teaches that polynucleotides encoding polypeptides (transgenes) are highly effective vectors for the delivery to and expression of transgenes in the central nervous system (CNS):
Adeno-associated virus (AAV) has been the vector of choice in recent clinical trials of neurological disease, including Parkinson’s and Alzheimer’s disease, due to the safety, efficacy, and stability of AAV gene transfer to the CNS. [abstract]
Weinberg teaches that AAVs often comprise promoters, promoter selection can affect transgene expression (Fig. 1), and that the inclusion of promoters in AAV vectors can enhance expression in specific target cells such as neurons:
some constitutive promoters, such as the hybrid chicken beta-actin (CBA) promoter lead to very high levels of primarily neuronal transgene expression [Fig. 1]
Weinberg does not teach the polynucleotide comprising glycine serine linkers.
Chen teaches that flexible glycine serine linkers are required for the successful construction of recombinant fusion proteins when the proteins require a certain degree of movement:
The successful construction of a recombinant fusion protein requires two indispensable elements: the component proteins and the linkers. [p. 1]
Flexible linkers are usually applied when the joined domains require a certain degree of movement or interaction. [p. 4]
The most commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker). An example of the most widely used flexible linker has the sequence of (Gly-Gly-Gly-Gly-Ser)n. [p. 4]
Weinberg, Bach, Chen and PGPUB946 do not teach wherein the second polypeptide part consists of or comprises the sequence HWLKV.
Dev teaches that PDZ domains are valuable drug targets, because molecules and peptides which specifically bind and block PDZ domains can interfere with protein interactions in disease:
Targeting the PDZ domain of proteins with peptides or small molecules is therefore of interest as a way to interfere with protein interactions in disease…One advantage of targeting PDZ domains is the potential to design drugs that are specific for a particular PDZ interaction. The most well-established method of interfering with PDZ interactions is the use of blocking peptides specific to the PDZ domain sequence. [abstract]
Alfonso teaches that inhibition of PICK1 interactions via a compound that specifically binds the PICK1 PDZ domain has therapeutic implications for the treatment of Alzheimer’s disease:
Amyloid beta (Ab), a key component in the pathophysiology of Alzheimer’s disease, is thought to target excitatory synapses early in the disease…Here we showed that the PDZ domain protein, protein interacting with C kinase 1 (PICK1), was required for Ab to weaken synapses…a novel small molecule (BIO922) discovered through structure- based drug design that targets the specific interactions between GluA2 and PICK1 blocked the effects of Ab on synapses and surface receptors. [abstract]
Our findings suggest that drugs targeting the interaction between GluA2 and PICK1 may be beneficial in offsetting the effects of elevated Ab, and therefore may warrant consideration in the therapeutics of Alzheimer’s disease. [p. 1232]
Erlendsson teaches that a DAT C5 ligand peptide of PICK1 comprising the Class II PBM amino acid sequence HWLKV specifically binds the PDZ domain of PICK1 with high affinity (“the peptides bind PICK1 PDZ”; p. 25330; see also Tables 1 and 5).
Kalandadze teaches the expression of a polypeptide in yeast cells wherein the polypeptide part comprises the amino acid sequence L-[X]6-L-[X]6-L-[X]6-L, wherein X is any proteinogenic or non-proteinogenic amino acid residue, and the expression of said polypeptide permits assembly of soluble oligomeric complexes in vivo:
The transmembrane regions were important for the assembly of DR2 molecules since the α and β chains did not assemble in mammalian or insect cells when the transmembrane regions were truncated. The leucine zipper dimerization motifs from the transcription factors Fos and Jun were therefore used to replace the hydrophobic transmembrane regions. Synthetic peptides of the Fos and Jun leucine zipper dimerization motif are known to assemble as stable, soluble heterodimers…The leucine zippers are characterized by five leucines that are spaced periodically at every seventh residue (heptad repeat); each heptad repeat contributes two turns of the α-helix (3.5 residues/turn). The leucine residues have a special function in leucine zipper dimerization and form the interface between the two α-helices in the coiled coil. The Fos/Jun heterodimer is soluble due to charged residues on the outer surface of the coiled coil…Use of the Fos and Jun leucine zipper dimerization motifs as a replacement of the hydrophobic transmembrane regions allowed the assembly and secretion of soluble HLA-DR2 in a yeast expression system/
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the polypeptide taught by Bach by substituting the non-polypeptide PEG linker with leucine zippers, as taught by PGPUB946, to yield a polypeptide that was both capable of forming homodimers and of being expressed from a single polynucleotide construct under the control of an appropriate promoter as taught by Weinberg, and thus easier to synthesize and express in target cells. It would also have been obvious to link the leucine zipper domain to the PBM by adding the flexible glycine serine linker such as GGGGS as taught by Chen, to achieve the predictable result of a fusion polypeptide with two domains able to move freely and thus successfully dimerize. Expression of the polypeptide would enable the artisan to ensure that the polypeptide is stably expressed in target cells of the CNS, thus eliminating the need for repeat administrations of the gene therapy for treatment of ongoing or chronic neurological conditions. The skilled artisan would have been motivated to express the polypeptide taught by Bach in an AAV vector and under the control of a promoter suitable for expression in the CNS based on Bach’s teachings that the dimeric polypeptide is a highly effective neuroprotective agent with therapeutic potential in stroke. The artisan would further have had a reasonable expectation of success based on Bach’s teachings that the dimeric polypeptide was a highly effective neuroprotective agent and based on Weinberg and Chen’s teachings of known effective methods for expression of transgenes (including those encoding fusion proteins) in the CNS, as described above.
Regarding the specific PBM and leucine zipper sequences claimed, it would further have been obvious to substitute the PBM sequence capable of specifically binding the PDZ domain of PSD-95 (as taught by Bach) with the PBM sequence capable of specifically binding the PDZ domain of PICK1, as taught by Erlendsson, to obtain the predictable result of a dimeric polypeptide capable of specifically binding the PDZ domain of PICK1. The skilled artisan would have been motivated to do so based on the teachings of Dev that peptides which specifically bind and block PDZ domains are valuable drug targets in general, and on the teachings of Alfonso that drugs targeting the PDZ domain of PICK1 and thus target the interactions between PICK1 and GluA2 are potential therapeutics of Alzheimer’s disease in particular. Furthermore, it would have been obvious to have substituted the generic leucine zipper domain as taught by PGPUB946 with the specific leucine zipper motif as taught by Kalandadze to achieve the predictable result of a dimeric polypeptide which was known to be soluble, amenable to in vivo expression from a polynucleotide, and effective at forming oligomeric structures in vivo.
Claims 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Bach et al. (of record) in view of Weinberg (of record), Chen, U.S. Patent Publication No. 2009/0305946 A1 (of record, herein PGPUB946), Dev (of record), Alfonso (of record), Erlendsson (of record),and Kalandadze as applied to claims 33, 40, 42-44 and 46-48, further in view of Mittl et al. (of record).
Bach, Weinberg, Chen, PGPUB946, Dev, Alfonso, Erlendsson and Kalandadze render obvious the polynucleotide encoding the polypeptide of claim 33, from which instantly rejected claims 35-37 depend, as described above.
Bach, Weinberg, Chen, PGPUB946, Dev, Alfonso, Erlendsson and Kalandadze:
wherein the first polypeptide part is selected from the group consisting of GCN4p1, GCN4p1(7P14P), and SSO10a (relevant to claim 35)
wherein the first polypeptide part comprises an alpha helix (relevant to claim 36)
wherein the homodimer of the first polypeptide part is formed as a coiled coil (relevant to claim 37)
Mittl teaches that leucine zippers such as the coiled-coil domain of GNC4 consist of intertwined alpha helices which form the coiled-coils when homodimerized (see Figure 1 and below):
Coiled coils, including leucine zippers, consist of two to five intertwined α-helices and are frequently found in oligomeric proteins such as transcription factors as well as motility and structural proteins...We used the two-stranded coiled-coil domain of the yeast transcription activator GCN4 [p. 2563]
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the polynucleotide of claim 33 as taught by Bach, Weinberg, Chen, PGPUB946, Dev, Alfonso, Erlendsson and Kalandadze to encode a polypeptide capable of forming a homodimer by specifically encoding the known element of a leucine zipper domain, which comprises alpha helices arranged in a coiled-coil domain. The skilled artisan would have recognized that leucine zipper domains are well-known components of oligomeric proteins and are capable of forming stable homodimers, as taught by Mittl. Therefore, one of ordinary skill would have predicted that modifying the first polypeptide to form a leucine zipper domain would have successfully resulted in a polypeptide capable of forming a stable homodimer.
Response to Arguments
Applicant's arguments filed 01/17/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s statement that, “The understood basis of each of these rejection is the office’s assertion that the inhibitor of Bach, linked to a leucine zipper motif of Dewji, by a glycine serine linker of Chen and expressed in a polynucleotide of Weinberg reads on the instant claim,” the Examiner has offered clarification of the assertion in the modified rejection above. Specifically, the inhibitor of Bach is provided to teach a polypeptide dimer structure comprising two PBMs for high affinity binding of multi-PDZ-domain proteins such as PSD-95, while PGPUB946 is provided to teach an alternative approach to polypeptide dimerization via leucine zipper motifs instead of the PEG linker taught by Bach. The thrust of Bach’s teachings are interpreted such that it is the bivalent interaction of two PBMs with the tandom PDZ1-2 domains of PSD-95 which is crucial to Bach’s invention, but that the particular manner in which the PBMs are dimerized is not, so long as the dimer is formed. Thus, the NPEG linker of Bach may be substituted with the known dimerization module of a leucine zipper (as taught by Dewji) to achieve effectively the same outcome, i.e., a dimer structure comprising the two PBMs capable of interacting with tandom PDZ domains. This substitution, when combined with the polypeptide glycine-serine linker as taught by Chen, would have permitted expression of the resulting construct from a polynucleotide as taught by Weinberg, and subsequent homodimerization of the resulting polypeptides as taught by PGPUB946. It is believed that this clarification addresses Applicant’s argument that, “the inhibitors of Bach cannot be expressed in a polynucleotide of Weinberg”, because the substitution of the PEG linker for the leucine zipper and glycine-serine linker would have converted Bach’s dimer to a full polypeptide structure, permitting easy expression of the entire construct from a polynucleotide transcript. It is also believed that the replacement of the NPEG linker of Bach with leucine zipper domains addresses Applicant’s arguments that, “neither the pentapeptides of Bach (which are not capable of forming a homodimer)…constitute a polypeptide part capable of forming a homodimer”, because the leucine zipper domains are polypeptide domains capable of forming homodimers.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/A.M.Z./Examiner, Art Unit 1636
/RICHARD A SCHNIZER/Primary Examiner, Art Unit 1635
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