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 .
Applicant’s election without traverse of group I and the species wherein the first click reagent is azide and the second click reagent is DBCO; a CRISPR associated protein 9 (Cas9), and a stem cell in the reply filed on 8/1/25 is acknowledged.
Claims 14, 15, 24, 25, 38, and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/1/25.
Improper Markush Rejection
Claims 11-13 and 18 are rejected on the judicially-created 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). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
With regards to the click reagents, the claims recite that the reagent is an azide, dibenzocyclooctyne (DBCO), transcyclooctene, tetrazine, norbornene, and any possible variants thereof. Each of the reagents have different structures and do not have identical activity.
With regards to the agents, the claims recite that the agent is selected from the group consisting of a small molecule, a nucleic acid, a protein or a peptide. The nucleic acid is a siRNA, shRNA, ribozyme RNA, iRNA, sgRNA, or miRNA. The protein or peptide is a transcriptional factor, a growth factor, a cytokine, an antibody, or a gene editing protein or peptide, wherein the gene editing protein or peptide is meganuclease, zinc finger nuclease (ZFN), transcription activator like effector-based nuclease (TALEN), or CRISPR associate protein (Cas), or wherein the protein or peptide is a CRISPR associate protein 9 (Cas9).
Each of these agents has a different structure and activity. None of the agents can be substituted for any of the other agents with expectation of identical activity. None of the agents have the same structure or function.
For example, the term “gRNA’ refers to an RNA that will bind to a Cas protein for the purpose of localizing that protein with a DNA or RNA target. In contrast, siRNAs do not bind to Cas proteins, but instead bind to Argonaute proteins and function to guide those proteins to targets. Accordingly, siRNAs and gRNAs do not have sufficiently similar structures to provide the same function because each has a structure that dictates that it must bind to a different protein effector molecule.
Therefore, the members of the Markush group lack any common substantial structural feature that provides a common use, and the group of alternatives is an improper Markush group. In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific recited reagent or agent is dependent upon the specific structure. There is no expectation that any one of the reagents or agents as claimed can be substituted for any of the other with a completely different structure with the expectation of the same activity.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one of the instant click reagents or agents would not be evidence against any of the remaining members that have completely different structures, act via different mechanisms, and do not have identical activity.
Response to Arguments
Applicant argues that the amendments to the claims have rendered the rejection moot. However, the claims recite a large multitude of agents that are not a proper Markush grouping, as explained above.
It is noted however that as instantly drafted, claim 1 link(s) the inventions of the rejected claims. The restriction requirement among the linked inventions is subject to the nonallowance of the linking claim(s), claim 1. Upon the allowance of the linking claim(s), the restriction requirement as to the linked inventions shall be withdrawn and any claim(s) depending from or otherwise including all the limitations of the allowable linking claim(s) will be entitled to examination in the instant application. Applicant(s) are advised that if any such claim(s) depending from or including all the limitations of the allowable linking claim(s) is/are presented in a continuation or divisional application, the claims of the continuation or divisional application may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Where a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. In re Ziegler, 44 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 8, 11-13, 16-21, and 60-62 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 claims are directed to a method of delivering an agent to a cell intracellularly, comprising contacting the cell coupled to a first click reagent with the agent coupled to a second click reagent, wherein the agents are DBCO and azide.
The specification does not adequately describe the genus of agents that have the structure to be delivered via the instantly recited system.
For example, Pickens et al. (Bioconjug Chem. 2018 March 21; 29(3): 686–701) teach that some click reagents are only able to deliver agents that are able to be solubilized by a click reagent that is an organic solvent (Table 3); and that using CuAAC as a click reaction may lead to side reactions such as oxidation of amino acids or small molecules, or reduction of cysteines (Table 3).
Pickens et al. teach: As the field continues to emerge, careful attention should be given to key parameters such as solubility and stability of reactants, which are often mismatched in terms of their physiochemical properties. In addition, variations in product solubility, size, charge, and stability should be more systematically investigated, since these features directly affect pharmacokinetics, pharmacodynamics, and safety (page 14).
Pickens et al. teach: When designing bioconjugates that utilize the AAC reaction, the chemical and physical stability of the biomolecule, linker, payload, and any intermediates or catalysts must be taken into consideration and monitored appropriately (page 10).
The claims encompass delivery of any agent, but without further description of the structure required for the agent to be functional within the recited system one would not be able to readily envision which agents have the required structure. DBCO and azide click reagents cannot necessarily deliver any agent, including those with competing nucleophiles or azide-reactive groups, thiols, agents with competing click chemistries, and substrates that are not compatible with aqueous SPAAC conditions.
Therefore, it was known in the art that not any combination of click reagents can deliver any agent. The specification does not adequately describe the structure required for the combinations of click reagents or for the agent to be delivered.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being agents that function as click reagents and variants thereof that have the required function.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for agents within the instant enormous genus that can be delivered via the instant system. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that the specification demonstrates that human dermal fibroblasts labeled with azide can be targeted with Cas9 coupled to DBCO. This species is not representative of the entire claimed genus.
Claims 1-6, 8, 11-13, 16-21, and 60-62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of contacting human dermal fibroblasts labeled with azide in vitro with DBCO-GFP/Cas9, does not reasonably provide enablement for a method of delivering any agent to a cell intracellularly, comprising contacting the cell coupled to azide with the agent coupled to DBCO, thereby delivering the agent to the cell intracellularly to any cell type. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant invention is drawn to a method of delivering any agent to a cell intracellularly, comprising contacting the cell coupled to azide with the agent coupled to DBCO, thereby delivering the agent to the cell intracellularly to any cell type.
The specification demonstrates incubation of human dermal fibroblasts labeled with azide in vitro with DBCO-GFP/Cas9 with a resultant GFP signal in almost all hDFs that were labeled with azide, which is not commensurate in scope with a method of delivering any agent to a cell intracellularly, comprising contacting the cell coupled to any first click reagent with the agent coupled to any second click reagent, wherein the second click reagent selectively reacts with the first click reagent coupled to the cell, thereby delivering the agent to the cell intracellularly to any cell type.
It was known in the art that broad delivery of any agent via any combination of click reagents was unpredictable. The claims are not enabled over the full scope.
The instant claims are not limited to any specific concentration of azide and DBCO that has demonstrated successful in vivo or in vitro delivery intracellularly of any possible agent.
Kim et al. (Chem. Sci., 2019, 10, 7835–7851) teach: Particularly, it is more delayed in drug delivery and therapy compared to imaging, because the required amount of molecules to be delivered for therapy is generally larger than that for imaging. Therefore, research using click chemistry in vivo for drug delivery and therapy is relatively unexplored, and more information is needed (page 7844).
Kim et al. teach: It is evident that the azide-DBCO reaction is slower than the Tz–TCO reaction. Some researchers have pointed out that it is too slow for pretargeting in vivo.
Kim et al. teach:. In addition, nanoparticles have longer circulation times than small molecules after i.v. injection. Thus, they could provide sufficient contact time among click molecules.
Kim et al. teach: Particularly, for applications in vivo, there is not sufficient time for conjugation in many situations, including i.v. injections. For these cases, the importance of reaction time should be considered in more detail (page 7848).
Kim et al. teach: In 2012, the Weissleder group pointed out that favorable pharmacokinetics and increased circulation time of injected molecules by conjugation with polymers of high molecular weight enhanced the reaction of click chemistry in vivo. After i.v. injection into mice, Tz groups showed a greater than 10-fold increase in the efficiency of click chemistry in vivo when they were attached to a 10 kDa dextran polymer compared to that of direct attachment to a fluorescent dye. Koo et al. have also shown the effects of pharmacokinetics of injected molecules on click chemistry in vivo. They conjugated Tz groups with fluorescent dyes of various chemical structures. In mice, the change of charge or hydrophobicity changed their biodistribution, circulation, and secretion. When they compared the efficiency of click chemistry in vivo using these molecules, they found that the efficiency was highly dependent upon the kinetics in vivo even though all of them contained the same Tz groups. These results suggest that we need to consider all molecules and situations carefully to use click chemistry successfully (page 7848).
Kim et al. teaches: Besides the second order reaction rate constant, the stability of click molecules under special conditions is also important to consider (page 7849).
There are many considerations known in the click chemistry field that need to be considered for each combination of click reagents and the agent to be delivered. There is a large amount of unpredictably in the art for a broad systemic method of delivering the instantly click reagents to deliver any possible agent intracellularly.
The claims encompass delivery of any agent, wherein the specification does not draw an adequate nexus between the instant system and the ability to deliver any possible agent. DBCO and azide click reagents cannot necessarily deliver any agent, including those with competing nucleophiles or azide-reactive groups, thiols, agents with competing click chemistries, and substrates that are not compatible with aqueous SPAAC conditions.
As outlined above, it is well known that there is a high level of unpredictability in the click chemistry art for therapeutic in vivo applications. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of delivering any agent via any combination of click reagents encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any agent in combination with the instantly recited click reagents in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful intracellular delivery. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, solubility of the molecule, stability of the molecule, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues that the specification demonstrates delivery of EGFP and human dermal fibroblasts labeled with azide can be targeted with Cas9 coupled to DBCO. This species is not representative of the entire claimed genus.
Applicant argues that the presence of inoperative embodiments does not necessarily render the claims nonenabled and that the standard is whether a skilled person could determine which embodiments would be inoperative or operative with expenditure of no more effort than is normally required in the art. In the instant case, it would certainly involve undue experimentation to determine which possible agents from any possible agent in existence could be successfully delivered via the instant system. As set forth in MPEP 2164.08(b), the scope of the claim may still not be enabled where undue experimentation is involved in determining those embodiments that are operable. The claims reading on significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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