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 .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 4/13/26 is acknowledged. The traversal is on the ground(s) that Applicant believes that it would not be unduly burdensome to perform a search on all of the claims together in the present application.
This is not found persuasive because Applicant is arguing elements of a restriction under US practice, and not Lack of Unity restriction practice. Under US restriction practice, a product and a process of using the product can be shown to be distinct inventions if either or both of the following can be shown: (A) the process of using as claimed can be practiced with another materially different product; or (B) the product as claimed can be used in a materially different process. However, the instant case has been filed as a national stage entry of a PCT international application. As shown in Example 1 in Chapter 10.21 of the PCT International Search and Preliminary Examination Guidelines (which can be found at http://www.wipo.int/export/sites/www/pct/en/texts/pdf/ispe.pdf), claims in different categories of inventions are permitted, but unity of invention is lacking if the technical feature shared by all of the claims is known in the art. Since claim 1 is anticipated by the prior art (Terakado, et al, 2010, US Patent No. 7,820,682), Unity of Invention is broken for all inventions, since they do not share the special technical feature disclosed in Isacoff in view of Maurel, because the special technical feature is disclosed in the combined teachings of those references.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
The preliminary amendments filed 4/13/26 are acknowledged. Claims 3-4, 9, 12, 21-22, 29-31, 33-34, 36-37 are cancelled. Claims 1-2, 5-8, 10-11, 13-20, 23-28, 32, and 35 are pending. Claims 19-20, 23-28, 32, and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/30/25.
Claims 1-2, 5-8, 10-11, 13-18 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 11/30/22 and 3/18/25 have been considered. Signed copies are enclosed.
Applicant is advised that the listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they will be considered.
Claim Objections
Claim 5 is objected to because of the following informalities: the term “selected from…or” should be amended to read “selected from…and”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-2, 5-8, 10-11, 13-18 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 claim(s) 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a system comprising components that are defined entirely by function, including an affinity agent that forms a covalent bond with a self-labeling protein tag, a photoisomerizable group, a ligand that binds to a target ligand-binding polypeptide, a self-labeling protein tag, and a membrane-anchoring polypeptide. These elements are combined to form a conjugate and a fusion polypeptide as components of the claimed system. While some species have been identified in the dependent claims for the various components, the specification has not provided either the structure that corresponds to the required structure or a representative number of species for the claimed genera that each potentially comprise thousands of possible chemical species that all have different structures and functionalities.
Additionally, the dependent claims recite a number of genera of compounds that are defined entirely by function, including agonists, antagonists, allosteric modulators, blockers, transcription regulator, cell-type specific promotor, dopamine derivatives or analogs that function as D1 dopamine receptor agonists, positive allosteric modulators of the D1 dopamine receptor, and others. These genera of molecules are defined entirely by their functions, and a correlating structure has not been identified. Further, the target molecule to be modulated by said genera has not been adequately described. The specification has also not provided sufficient species that are representative of the breadth of the claimed genera.
Also, it is noted that several proteins with specific functions, including a self-labeling protein tag, a target ligand binding polypeptide, and a membrane anchoring polypeptide are included in the inadequately described genera.
The system components, and therefore necessarily the system itself, have no correlation between their structure and function. The claim requires that the system components exhibit specific functional characteristics, but the specification provides no guidance regarding which proteins, small molecules, nucleic acids, antibodies, antibody fragments, or other biological or chemical species are capable of the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed system conjugates and fusion polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Regarding the encompassed protein components required to possess specific functional characteristics, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional system components that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of agents encompassed by the instant claims (see e.g. page 661, left column).
Regarding small molecule inhibitors of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al (Curr Med Chem. 2008;15(1):37-46), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind JAK or STAT, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al (J. Med. Chem., 2014, 57 (12), pp 5023–5038), even when guided by structural data, developing selective JAK structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular JAK or STAT protein family member, or treat disease.
Regarding nucleic acid based agents, the efficacy of any possible DNA or RNA based modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al (Advanced Drug Delivery Reviews 59 (2007) 75–86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), and the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based agents will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13). Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid functions could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would possess the required functional characteristics.
It is known for proteins, albeit not in all cases, that amino acid addition(s), substitution(s) or deletion(s) can destroy the function of the epitope or abolish its ability. This lack of predictability of the relationship between the protein sequence and the immunogenic epitope function is well documented by Mateu et al. (Mateu MG, et. al. Eur J Immunol. 1992 Jun;22(6):1385-9.) and Greenspan et al. (Greenspan NS, Di Cera E. Defining epitopes: It's not as easy as it seems. Nat Biotechnol. 1999 Oct;17(10):936-7.). The effects of these changes are largely unpredictable as to which ones have a significant effect versus not.
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of variants that have specific required functions. Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Therefore, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that the instant disclosure does not meet the written description provision of 35 USC 112(a).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-2, 5-8, 10-11, 13-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “a target ligand-binding polypeptide.” The term “target” in claim 1is a relative term which renders the claim indefinite. The term “target” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 1 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of a fusion polypeptide and a recombinant expression vector is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the fusion polypeptide is a protein that comprises amino acids and functions as a protein, while the recombinant expression vector comprises nucleic acids and functions to encode a polypeptide. The two molecule types do not share any structural similarity and are not functionally equivalent. They also do not share a common use due to the differences in structure and biological function between the two types of molecules.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim 1 recites the term “self-labeling protein tag.” The specification does not define the required characteristics for this protein tag, and the scope of the encompassed genus of protein tags is indefinite.
The term “agonist” “antagonist” “allosteric modulator” and “blocker” in claim 6 are relative terms which renders the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, the claim does not identify to what molecule the “agonist” “antagonist” “allosteric modulator” or “blocker” must perform its function. Without knowing what molecule is being targeted, there is no way to identify a molecule in any of the “agonist” “antagonist” “allosteric modulator” and “blocker” genera. These terms are
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 8 recites the broad recitation “glutamate receptor”, and the claim also recites species of glutamate receptors, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term “positive” in claim 11 is a relative term which renders the claim indefinite. The term “positive” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The term “cell-type specific” in claim 17 is a relative term which renders the claim indefinite. The term “cell-type” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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) 1-2, 5-8, 10-11, 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Isacoff et al (WO 2019/060785 A1; filed 9/21/18; published 3/28/19; hereinafter referred to as “Isacoff I”) in view of Isacoff et al (US 2015/0224193 A1; filed 1/8/15; published 8/13/15; hereinafter referred to as “Isacoff II”)
Instant claim 1 is directed to a system comprising: a) a conjugate comprising: i) an affinity agent that forms a covalent bond with a self-labeling protein tag; ii) a linker; iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide; and b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; ii) a peptide linker; and iii) a membrane-anchoring polypeptide.
Instant claim 2 is directed to the system of claim 1, wherein the affinity agent comprises a moiety selected from a benzylguanine, a chloroalkane, and a benzylcytosine.
Instant claim 5 is directed to the system of claim 1, wherein the photoisomerizable group comprises a moiety selected from an azobenzene, a cyclic azobenzene, an azoheteroarene, a fulgide, a spiropyran, a triphenyl methane, a thioindigo, a diarylethene, and or an overcrowded alkene.
Instant claim 6 is directed to the system of claim 1, wherein the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker.
Instant claim 7 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is selected from a transcription regulator, an ion channel, a cation channel, a ligand-gated ion channel, a voltage-gated ion channel, a quorum sensor, a pheromone receptor, a neurotransmitter receptor, or a G-protein-coupled receptor.
Instant claim 8 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor, a D2 dopamine receptor, a glutamate receptor, a metabotropic glutamate receptor, an ionotropic glutamate receptor, an ionotropic nicotinic acetylcholine receptor, an ionotropic GABA-A receptor, a metabotropic GABA-B receptor, a metabotropic dopamine receptor, an ionotropic purinergic P2X receptor, a metabotropic purinergic P2Y receptor, a metabotropic serotonin receptor, an ionotropic serotonin receptor, an ionotropic glycine receptor, a cation channel, a potassium channel, a calcium channel, a sodium channel, a proton channel, an anion channel, or a chloride channel.
Instant claim 10 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor.
Instant claim 11 is directed to the system of claim 10, wherein the ligand is selected from dopamine, er a dopamine derivative or analog that functions as a D1 dopamine receptor agonist, or a positive allosteric modulator of the D1 dopamine receptor.
Instant claim 13 is directed to the system of claim 1, wherein the linker comprises poly(ethylene glycol).
Instant claim 14 is directed to the system of claim 1, wherein the self-labeling protein tag comprises: a) an amino acid sequence having at least 80% amino acid sequence identity to the SNAP polypeptide amino acid sequence set forth in SEQ ID NO:1; b) an amino acid sequence having at least 80% amino acid sequence identity to the CLIP polypeptide amino acid sequence set forth in SEQ ID NO:2; or c) an amino acid sequence having at least 80% amino acid sequence identity to the HALO polypeptide amino acid sequence set forth in SEQ ID NO:3.
Instant claim 15 is directed to the system of claim 1, wherein the fusion polypeptide comprises an endoplasmic reticulum (ER) export signal peptide.
Instant claim 16 is directed to the system of claim 1, wherein the peptide linker comprises the amino acid sequence EAAAK (SEQ ID NO:13).
Instant claim 17 is directed to the system of claim 1, wherein the nucleotide sequence encoding the fusion polypeptide is operably linked to a cell type-specific promoter.
Instant claim 18 is directed to the system of claim 17, wherein the promoter is a dopamine-1 receptor promoter.
Isacoff I teaches a system comprising: a) a conjugate comprising (claim 1 "A conjugate comprising:"): i) an affinity agent that forms a covalent bond with a self-labeling protein tag (para [00143] "a conjugate of the present disclosure comprises: i) a moiety that covalently links to a SNAP tag [see para [00107], instant specification):; ii} a linker (claim 1 "A conjugate comprising: ... a linker; and"); iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide (para (00111] "a photoisomerizable regulator present in a conjugate of the present disclosure comprises: i) a photoisomerizable group; and ii} a ligand that binds to a target ligand- binding polypeptide."); b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag, a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further shows the fusion proteins as anchored to the plasma membrane (see e.g. Figure 1 and 3). Isacoff I teaches that the conjugate can comprise benzylguanine (para [0143]). The conjugate can comprise an azobenzene for the photoisomerizable group (para [0145]). The ligand can be an agonist (para [0266]). The target ligand-binding polypeptides can include a G protein coupled receptor or cation channel, among others (para [0267]). The linker can comprise polyethylene glycol (para [0070]).
Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the fusion protein comprises a membrane-anchoring polypeptide.
Isacoff II teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para (0113] "A change in the wavelength and/or intensity of light (DELTA_lamda) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). The ligands are intended to bind to membrane receptors, and the ligands bind soluble or membrane-bound or extracellular matrix-bound small molecules or proteins (para [0096]).
Based on the combined teachings of the references, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease; b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag. a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the antibody of the SNAP-affinity agent fusion is b)- ii) an antibody specific for the D1 dopamine receptor, however. Isacoff I teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para [0113] "A change in the wavelength and/or intensity of light (.DELTA .. lamda.) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). Based on the teaching of Isacoff II, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease. Further, it would be obvious to include a membrane-anchoring polypeptide with the fusion protein to ensure that targeting of the D1 receptor could physically occur, given that the D1 receptor is a membrane bound receptor.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claim(s) 1-2, 5-8, 10-11, 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Isacoff et al (WO 2019/060785 A1; filed 9/21/18; published 3/28/19; hereinafter referred to as “Isacoff I”) in view of Isacoff et al (US 2015/0224193 A1; filed 1/8/15; published 8/13/15; hereinafter referred to as “Isacoff II”) further in view of Cosson et al (Trends in Cell Biology, October 2013, Vol. 23, No. 10; hereinafter referred to as “Cosson”).
Instant claim 1 is directed to a system comprising: a) a conjugate comprising: i) an affinity agent that forms a covalent bond with a self-labeling protein tag; ii) a linker; iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide; and b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; ii) a peptide linker; and iii) a membrane-anchoring polypeptide.
Instant claim 2 is directed to the system of claim 1, wherein the affinity agent comprises a moiety selected from a benzylguanine, a chloroalkane, and a benzylcytosine.
Instant claim 5 is directed to the system of claim 1, wherein the photoisomerizable group comprises a moiety selected from an azobenzene, a cyclic azobenzene, an azoheteroarene, a fulgide, a spiropyran, a triphenyl methane, a thioindigo, a diarylethene, and or an overcrowded alkene.
Instant claim 6 is directed to the system of claim 1, wherein the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker.
Instant claim 7 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is selected from a transcription regulator, an ion channel, a cation channel, a ligand-gated ion channel, a voltage-gated ion channel, a quorum sensor, a pheromone receptor, a neurotransmitter receptor, or a G-protein-coupled receptor.
Instant claim 8 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor, a D2 dopamine receptor, a glutamate receptor, a metabotropic glutamate receptor, an ionotropic glutamate receptor, an ionotropic nicotinic acetylcholine receptor, an ionotropic GABA-A receptor, a metabotropic GABA-B receptor, a metabotropic dopamine receptor, an ionotropic purinergic P2X receptor, a metabotropic purinergic P2Y receptor, a metabotropic serotonin receptor, an ionotropic serotonin receptor, an ionotropic glycine receptor, a cation channel, a potassium channel, a calcium channel, a sodium channel, a proton channel, an anion channel, or a chloride channel.
Instant claim 10 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor.
Instant claim 11 is directed to the system of claim 10, wherein the ligand is selected from dopamine, er a dopamine derivative or analog that functions as a D1 dopamine receptor agonist, or a positive allosteric modulator of the D1 dopamine receptor.
Instant claim 13 is directed to the system of claim 1, wherein the linker comprises poly(ethylene glycol).
Instant claim 14 is directed to the system of claim 1, wherein the self-labeling protein tag comprises: a) an amino acid sequence having at least 80% amino acid sequence identity to the SNAP polypeptide amino acid sequence set forth in SEQ ID NO:1; b) an amino acid sequence having at least 80% amino acid sequence identity to the CLIP polypeptide amino acid sequence set forth in SEQ ID NO:2; or c) an amino acid sequence having at least 80% amino acid sequence identity to the HALO polypeptide amino acid sequence set forth in SEQ ID NO:3.
Instant claim 15 is directed to the system of claim 1, wherein the fusion polypeptide comprises an endoplasmic reticulum (ER) export signal peptide.
Instant claim 16 is directed to the system of claim 1, wherein the peptide linker comprises the amino acid sequence EAAAK (SEQ ID NO:13).
Instant claim 17 is directed to the system of claim 1, wherein the nucleotide sequence encoding the fusion polypeptide is operably linked to a cell type-specific promoter.
Instant claim 18 is directed to the system of claim 17, wherein the promoter is a dopamine-1 receptor promoter.
Isacoff I teaches a system comprising: a) a conjugate comprising (claim 1 "A conjugate comprising:"): i) an affinity agent that forms a covalent bond with a self-labeling protein tag (para [00143] "a conjugate of the present disclosure comprises: i) a moiety that covalently links to a SNAP tag [see para [00107], instant specification):; ii} a linker (claim 1 "A conjugate comprising: ... a linker; and"); iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide (para (00111] "a photoisomerizable regulator present in a conjugate of the present disclosure comprises: i) a photoisomerizable group; and ii} a ligand that binds to a target ligand- binding polypeptide."); b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag, a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further shows the fusion proteins as anchored to the plasma membrane (see e.g. Figure 1 and 3). Isacoff I teaches that the conjugate can comprise benzylguanine (para [0143]). The conjugate can comprise an azobenzene for the photoisomerizable group (para [0145]). The ligand can be an agonist (para [0266]). The target ligand-binding polypeptides can include a G protein coupled receptor or cation channel, among others (para [0267]). The linker can comprise polyethylene glycol (para [0070]).
Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the fusion protein comprises a membrane-anchoring polypeptide.
Isacoff II teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para (0113] "A change in the wavelength and/or intensity of light (DELTA_lamda) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). The ligands are intended to bind to membrane receptors, and the ligands bind soluble or membrane-bound or extracellular matrix-bound small molecules or proteins (para [0096]).
Based on the combined teachings of the references, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease; b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag. a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the antibody of the SNAP-affinity agent fusion is b)- ii) an antibody specific for the D1 dopamine receptor, however. Isacoff I teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para [0113] "A change in the wavelength and/or intensity of light (.DELTA .. lamda.) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). Based on the teaching of Isacoff II, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease. Further, it would be obvious to include a membrane-anchoring polypeptide with the fusion protein to ensure that targeting of the D1 receptor could physically occur, given that the D1 receptor is a membrane bound receptor.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Isacoff I and Isacoff II fail to teach the inclusion of an endoplasmic reticulum (ER) export signal.
Cosson teaches that transmembrane domains of proteins can lead to ER retention and ER-associated degradation (ERAD) before the protein can reach the cell surface (see e.g. page 511, right column).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to include an ER export signal peptide in the fusion protein of Isacoff I combined with Isacoff II to ensure that the proteins are not degraded before reaching the surface of the cell, where they would be able to engage in ligand binding. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Cosson shows that ER retention and resulting degradation were known to occur for transmembrane proteins. One of skill in the art would be motivated to ensure that the protein was exported from the ER to escape premature degradation. Adding such a peptide sequence would be within a known variation in the art, and would be achievable with conventional molecular biology techniques. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claim(s) 1-2, 5-8, 10-11, 13-14, 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Isacoff et al (WO 2019/060785 A1; filed 9/21/18; published 3/28/19; hereinafter referred to as “Isacoff I”) in view of Isacoff et al (US 2015/0224193 A1; filed 1/8/15; published 8/13/15; hereinafter referred to as “Isacoff II”) further in view of Chen (Adv Drug Deliv Rev. 2013 October 15; 65(10): 1357-1369; hereinafter referred to as “Chen”)
Instant claim 1 is directed to a system comprising: a) a conjugate comprising: i) an affinity agent that forms a covalent bond with a self-labeling protein tag; ii) a linker; iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide; and b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; ii) a peptide linker; and iii) a membrane-anchoring polypeptide.
Instant claim 2 is directed to the system of claim 1, wherein the affinity agent comprises a moiety selected from a benzylguanine, a chloroalkane, and a benzylcytosine.
Instant claim 5 is directed to the system of claim 1, wherein the photoisomerizable group comprises a moiety selected from an azobenzene, a cyclic azobenzene, an azoheteroarene, a fulgide, a spiropyran, a triphenyl methane, a thioindigo, a diarylethene, and or an overcrowded alkene.
Instant claim 6 is directed to the system of claim 1, wherein the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker.
Instant claim 7 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is selected from a transcription regulator, an ion channel, a cation channel, a ligand-gated ion channel, a voltage-gated ion channel, a quorum sensor, a pheromone receptor, a neurotransmitter receptor, or a G-protein-coupled receptor.
Instant claim 8 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor, a D2 dopamine receptor, a glutamate receptor, a metabotropic glutamate receptor, an ionotropic glutamate receptor, an ionotropic nicotinic acetylcholine receptor, an ionotropic GABA-A receptor, a metabotropic GABA-B receptor, a metabotropic dopamine receptor, an ionotropic purinergic P2X receptor, a metabotropic purinergic P2Y receptor, a metabotropic serotonin receptor, an ionotropic serotonin receptor, an ionotropic glycine receptor, a cation channel, a potassium channel, a calcium channel, a sodium channel, a proton channel, an anion channel, or a chloride channel.
Instant claim 10 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor.
Instant claim 11 is directed to the system of claim 10, wherein the ligand is selected from dopamine, er a dopamine derivative or analog that functions as a D1 dopamine receptor agonist, or a positive allosteric modulator of the D1 dopamine receptor.
Instant claim 13 is directed to the system of claim 1, wherein the linker comprises poly(ethylene glycol).
Instant claim 14 is directed to the system of claim 1, wherein the self-labeling protein tag comprises: a) an amino acid sequence having at least 80% amino acid sequence identity to the SNAP polypeptide amino acid sequence set forth in SEQ ID NO:1; b) an amino acid sequence having at least 80% amino acid sequence identity to the CLIP polypeptide amino acid sequence set forth in SEQ ID NO:2; or c) an amino acid sequence having at least 80% amino acid sequence identity to the HALO polypeptide amino acid sequence set forth in SEQ ID NO:3.
Instant claim 15 is directed to the system of claim 1, wherein the fusion polypeptide comprises an endoplasmic reticulum (ER) export signal peptide.
Instant claim 16 is directed to the system of claim 1, wherein the peptide linker comprises the amino acid sequence EAAAK (SEQ ID NO:13).
Instant claim 17 is directed to the system of claim 1, wherein the nucleotide sequence encoding the fusion polypeptide is operably linked to a cell type-specific promoter.
Instant claim 18 is directed to the system of claim 17, wherein the promoter is a dopamine-1 receptor promoter.
Isacoff I teaches a system comprising: a) a conjugate comprising (claim 1 "A conjugate comprising:"): i) an affinity agent that forms a covalent bond with a self-labeling protein tag (para [00143] "a conjugate of the present disclosure comprises: i) a moiety that covalently links to a SNAP tag [see para [00107], instant specification):; ii} a linker (claim 1 "A conjugate comprising: ... a linker; and"); iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide (para (00111] "a photoisomerizable regulator present in a conjugate of the present disclosure comprises: i) a photoisomerizable group; and ii} a ligand that binds to a target ligand- binding polypeptide."); b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag, a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further shows the fusion proteins as anchored to the plasma membrane (see e.g. Figure 1 and 3). Isacoff I teaches that the conjugate can comprise benzylguanine (para [0143]). The conjugate can comprise an azobenzene for the photoisomerizable group (para [0145]). The ligand can be an agonist (para [0266]). The target ligand-binding polypeptides can include a G protein coupled receptor or cation channel, among others (para [0267]). The linker can comprise polyethylene glycol (para [0070]).
Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the fusion protein comprises a membrane-anchoring polypeptide.
Isacoff II teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para (0113] "A change in the wavelength and/or intensity of light (DELTA_lamda) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). The ligands are intended to bind to membrane receptors, and the ligands bind soluble or membrane-bound or extracellular matrix-bound small molecules or proteins (para [0096]).
Based on the combined teachings of the references, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease; b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag. a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the antibody of the SNAP-affinity agent fusion is b)- ii) an antibody specific for the D1 dopamine receptor, however. Isacoff I teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para [0113] "A change in the wavelength and/or intensity of light (.DELTA .. lamda.) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). Based on the teaching of Isacoff II, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease. Further, it would be obvious to include a membrane-anchoring polypeptide with the fusion protein to ensure that targeting of the D1 receptor could physically occur, given that the D1 receptor is a membrane bound receptor.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Isacoff I and Isacoff II fail to teach the linker sequence of EAAAK.
Chen teaches that an indispensable component of recombinant fusion proteins is the liker between protein components (abstract). Linkers containing the EAAAK sequence improved expression and bioactivity of fusion proteins (page 9, section 5.2; page 10, section 5.3).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to use the linker sequence of EAAAK in the proteins of Isacoff I combined with Isacoff II to increase expression and bioactivity of the fusion protein. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Cosson shows that ER retention and resulting degradation were known to occur for transmembrane proteins. One of skill in the art would be motivated to ensure that recombinant proteins intended for biological function have maximum expression and bioactivity. Adding such a peptide sequence would be within a known variation in the art, and would be achievable with conventional molecular biology techniques. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claim(s) 1-2, 5-8, 10-11, 13-14, 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Isacoff et al (WO 2019/060785 A1; filed 9/21/18; published 3/28/19; hereinafter referred to as “Isacoff I”) in view of Isacoff et al (US 2015/0224193 A1; filed 1/8/15; published 8/13/15; hereinafter referred to as “Isacoff II”) further in view of Brown (Chapter 10: Constructing Strong Cell Type-Specific Promoters Through Informed Design. In: Gould, D. (eds) Mammalian Synthetic Promoters. Methods in Molecular Biology, vol 1651. Humana, New York, NY.; Aug 2017; hereinafter referred to as “Brown”)
Instant claim 1 is directed to a system comprising: a) a conjugate comprising: i) an affinity agent that forms a covalent bond with a self-labeling protein tag; ii) a linker; iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide; and b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; ii) a peptide linker; and iii) a membrane-anchoring polypeptide.
Instant claim 2 is directed to the system of claim 1, wherein the affinity agent comprises a moiety selected from a benzylguanine, a chloroalkane, and a benzylcytosine.
Instant claim 5 is directed to the system of claim 1, wherein the photoisomerizable group comprises a moiety selected from an azobenzene, a cyclic azobenzene, an azoheteroarene, a fulgide, a spiropyran, a triphenyl methane, a thioindigo, a diarylethene, and or an overcrowded alkene.
Instant claim 6 is directed to the system of claim 1, wherein the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker.
Instant claim 7 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is selected from a transcription regulator, an ion channel, a cation channel, a ligand-gated ion channel, a voltage-gated ion channel, a quorum sensor, a pheromone receptor, a neurotransmitter receptor, or a G-protein-coupled receptor.
Instant claim 8 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor, a D2 dopamine receptor, a glutamate receptor, a metabotropic glutamate receptor, an ionotropic glutamate receptor, an ionotropic nicotinic acetylcholine receptor, an ionotropic GABA-A receptor, a metabotropic GABA-B receptor, a metabotropic dopamine receptor, an ionotropic purinergic P2X receptor, a metabotropic purinergic P2Y receptor, a metabotropic serotonin receptor, an ionotropic serotonin receptor, an ionotropic glycine receptor, a cation channel, a potassium channel, a calcium channel, a sodium channel, a proton channel, an anion channel, or a chloride channel.
Instant claim 10 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor.
Instant claim 11 is directed to the system of claim 10, wherein the ligand is selected from dopamine, er a dopamine derivative or analog that functions as a D1 dopamine receptor agonist, or a positive allosteric modulator of the D1 dopamine receptor.
Instant claim 13 is directed to the system of claim 1, wherein the linker comprises poly(ethylene glycol).
Instant claim 14 is directed to the system of claim 1, wherein the self-labeling protein tag comprises: a) an amino acid sequence having at least 80% amino acid sequence identity to the SNAP polypeptide amino acid sequence set forth in SEQ ID NO:1; b) an amino acid sequence having at least 80% amino acid sequence identity to the CLIP polypeptide amino acid sequence set forth in SEQ ID NO:2; or c) an amino acid sequence having at least 80% amino acid sequence identity to the HALO polypeptide amino acid sequence set forth in SEQ ID NO:3.
Instant claim 15 is directed to the system of claim 1, wherein the fusion polypeptide comprises an endoplasmic reticulum (ER) export signal peptide.
Instant claim 16 is directed to the system of claim 1, wherein the peptide linker comprises the amino acid sequence EAAAK (SEQ ID NO:13).
Instant claim 17 is directed to the system of claim 1, wherein the nucleotide sequence encoding the fusion polypeptide is operably linked to a cell type-specific promoter.
Instant claim 18 is directed to the system of claim 17, wherein the promoter is a dopamine-1 receptor promoter.
Isacoff I teaches a system comprising: a) a conjugate comprising (claim 1 "A conjugate comprising:"): i) an affinity agent that forms a covalent bond with a self-labeling protein tag (para [00143] "a conjugate of the present disclosure comprises: i) a moiety that covalently links to a SNAP tag [see para [00107], instant specification):; ii} a linker (claim 1 "A conjugate comprising: ... a linker; and"); iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide (para (00111] "a photoisomerizable regulator present in a conjugate of the present disclosure comprises: i) a photoisomerizable group; and ii} a ligand that binds to a target ligand- binding polypeptide."); b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag, a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further shows the fusion proteins as anchored to the plasma membrane (see e.g. Figure 1 and 3). Isacoff I teaches that the conjugate can comprise benzylguanine (para [0143]). The conjugate can comprise an azobenzene for the photoisomerizable group (para [0145]). The ligand can be an agonist (para [0266]). The target ligand-binding polypeptides can include a G protein coupled receptor or cation channel, among others (para [0267]). The linker can comprise polyethylene glycol (para [0070]).
Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the fusion protein comprises a membrane-anchoring polypeptide.
Isacoff II teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para (0113] "A change in the wavelength and/or intensity of light (DELTA_lamda) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). The ligands are intended to bind to membrane receptors, and the ligands bind soluble or membrane-bound or extracellular matrix-bound small molecules or proteins (para [0096]).
Based on the combined teachings of the references, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease; b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; and ii) an antibody (para [00238] "Where the affinity agent is a polypeptide (e.g., an antibody). the affinity agent can be coupled (e.g., covalently linked to) a photoisomerizable regulator by use of a HALO-tag, a SNAP tag, a CLIP tag. a lumio tag. and the like. For example, a nucleic acid comprising a nucleotide sequence encoding a SNAP tag fused in-frame to a single chain antibody, a single- domain antibody, or a nanobody is introduced into a cell for production of the SNAPantibody fusion protein."). Isacoff I further teaches that the target ligand-binding polypeptide can be a neurotransmitter receptor (para [00267] ''Target ligand-binding polypeptides include ... a neurotransmitter receptor"), but does not expressly teach that the a)-iv) ligand binds to a D1 dopamine receptor or that the antibody of the SNAP-affinity agent fusion is b)- ii) an antibody specific for the D1 dopamine receptor, however. Isacoff I teaches protein regulators comprising photoisomerizable groups that bind to targets in the presence of light (para (0059] "a synthetic regulator of protein function, light-regulated polypeptides comprising the regulator, and devices comprising the polypeptides. A subject synthetic protein regulator comprises: a) a linker domain, comprising a moiety that provides for covalent linkage to an amino acid side chain; b) a photoisomerizable group; and c} a ligand that binds to a ligand binding site) regulator.", para [0113] "A change in the wavelength and/or intensity of light (.DELTA .. lamda.) to which the light-regulated polypeptide is exposed results in a change in ligand binding to a ligand-binding site of the light-regulated polypeptide"}, and further teaches that dopamine receptors may be targets of the ligand (para [0124] Suitable ligand-binding polypeptides include ... ion channels; transporters; receptors", para [01281 Receptors include a dopamine receptor"). Based on the teaching of Isacoff II, it would have been obvious to an artisan of ordinary skill in the art to include dopamine receptors among the target ligand-binding polypeptides of Isacoff I, because said system comprising regulatable D1 dopamine receptors would be valuable for studies involving D1 dopamine receptors or potentially treatment for D1 receptor related disease. Further, it would be obvious to include a membrane-anchoring polypeptide with the fusion protein to ensure that targeting of the D1 receptor could physically occur, given that the D1 receptor is a membrane bound receptor.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Isacoff I and Isacoff II fail to teach the use of a cell-specific promoter for producing recombinant proteins from polynucleotides.
Brown teaches that to achieve high levels of transcriptional activity within a particular cell type, synthetic promoters must be specifically designed to harness those cells discrete repertoire of available transcription factors (abstract). Brown advocates that for optimal performance, promoters should be specifically constructed to function within discrete host cell types (page 131, Introduction).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to use a cell-type specific promotor to increase performance of expression systems and to harness the transcription factors in the targeted cell types. In particular, dopamine receptors are expressed in several specific tissue types, including in the brain, and use of specific transcription systems offers the ability to target specific tissues according to the teachings of Brown. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Brown teaches the use of cell-specific promotors to increase transcription in a targeted cell type. One of skill in the art would be motivated to ensure that recombinant proteins intended for biological function in a specific target cell or tissue have maximum expression. Adding such a promoter sequence would be within a known variation in the art, and would be achievable with conventional molecular biology techniques. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
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.
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Claim 1-2, 5-8, 10-11, 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/857,145 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claim 1 is directed to a system comprising: a) a conjugate comprising: i) an affinity agent that forms a covalent bond with a self-labeling protein tag; ii) a linker; iii) a photoisomerizable group; and iv) a ligand that binds to a target ligand-binding polypeptide; and b) a fusion polypeptide, or a recombinant expression vector comprising a nucleotide sequence encoding the fusion polypeptide, wherein the fusion polypeptide comprises: i) a self-labeling protein tag; ii) a peptide linker; and iii) a membrane-anchoring polypeptide.
Instant claim 2 is directed to the system of claim 1, wherein the affinity agent comprises a moiety selected from a benzylguanine, a chloroalkane, and a benzylcytosine.
Instant claim 5 is directed to the system of claim 1, wherein the photoisomerizable group comprises a moiety selected from an azobenzene, a cyclic azobenzene, an azoheteroarene, a fulgide, a spiropyran, a triphenyl methane, a thioindigo, a diarylethene, and or an overcrowded alkene.
Instant claim 6 is directed to the system of claim 1, wherein the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker.
Instant claim 7 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is selected from a transcription regulator, an ion channel, a cation channel, a ligand-gated ion channel, a voltage-gated ion channel, a quorum sensor, a pheromone receptor, a neurotransmitter receptor, or a G-protein-coupled receptor.
Instant claim 8 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor, a D2 dopamine receptor, a glutamate receptor, a metabotropic glutamate receptor, an ionotropic glutamate receptor, an ionotropic nicotinic acetylcholine receptor, an ionotropic GABA-A receptor, a metabotropic GABA-B receptor, a metabotropic dopamine receptor, an ionotropic purinergic P2X receptor, a metabotropic purinergic P2Y receptor, a metabotropic serotonin receptor, an ionotropic serotonin receptor, an ionotropic glycine receptor, a cation channel, a potassium channel, a calcium channel, a sodium channel, a proton channel, an anion channel, or a chloride channel.
Instant claim 10 is directed to the system of claim 1, wherein the target ligand-binding polypeptide is a D1 dopamine receptor.
Instant claim 11 is directed to the system of claim 10, wherein the ligand is selected from dopamine, er a dopamine derivative or analog that functions as a D1 dopamine receptor agonist, or a positive allosteric modulator of the D1 dopamine receptor.
Instant claim 13 is directed to the system of claim 1, wherein the linker comprises poly(ethylene glycol).
Instant claim 14 is directed to the system of claim 1, wherein the self-labeling protein tag comprises: a) an amino acid sequence having at least 80% amino acid sequence identity to the SNAP polypeptide amino acid sequence set forth in SEQ ID NO:1; b) an amino acid sequence having at least 80% amino acid sequence identity to the CLIP polypeptide amino acid sequence set forth in SEQ ID NO:2; or c) an amino acid sequence having at least 80% amino acid sequence identity to the HALO polypeptide amino acid sequence set forth in SEQ ID NO:3.
Instant claim 15 is directed to the system of claim 1, wherein the fusion polypeptide comprises an endoplasmic reticulum (ER) export signal peptide.
Instant claim 16 is directed to the system of claim 1, wherein the peptide linker comprises the amino acid sequence EAAAK (SEQ ID NO:13).
Instant claim 17 is directed to the system of claim 1, wherein the nucleotide sequence encoding the fusion polypeptide is operably linked to a cell type-specific promoter.
Instant claim 18 is directed to the system of claim 17, wherein the promoter is a dopamine-1 receptor promoter.
The copending application claims a conjugate comprising a dopamine receptor ligand, a ligand, a hydrophobic moiety, and a halogen-containing substrate, and a fusion protein or recombinant vector encoding the fusion protein, wherein the fusion protein comprises a self-labeling protein tag, a peptide linker and a membrane-anchoring polypeptide (see e.g. claim 1). The hydrophobic moiety can be an azobenzene and other moieties recited in the instant claims (see e.g. claim 4). The linker can comprise a polyethylene glycol (see e.g. claim 8). The azobenzene moiety can be photoisomerizable (see e.g. claim 10). The DRL can function as a positive allosteric modulator of the D2 dopamine receptor (see e.g. claim 12). The DRL can be a dopamine receptor ligand, or a D1 dopamine receptor antagonist (see e.g. claims 22-23). The self-labeling protein tag can be the same sequences as the instant claims (see e.g. claim 25). The fusion protein can comprise an ER export signal peptide (see e.g. claim 26). The peptide linker can comprise the EAAAK sequence (see e.g. claim 27). The expression vector can comprise a cell-type specific promotor, such as a dopamine-1 receptor promotor (see e.g. claim 29).
The copending claims anticipate the instant claims, but differ in scope. The copending claims recite species of the instant claims, while the instant claims are directed to the genus of systems that can comprise other species in addition to those recited in the copending application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
Prosecution Insights