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 .
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 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.
Response to Restriction/Election
Applicant’s election of “antibody” for bait molecule “G”, “benzophenone” for warhead “W”, “biotin derivative” for tag “B”, “click chemistry-based moiety” for cross-linkable group “K”, “proteolytically cleavable peptide sequence” for cleavage site “A”, formula (I-1)
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for “L1 portion” and formula (I-2)
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for “L2 portion”, and click chemistry-based moiety and plurality of glycine residues and/or plurality of methionine residues for cross-linkable moiety and warhead binding region respectively for “connector”, in response to species requirement is acknowledged. Applicant mentioned that claims 4 and 16-17 do not read on the elected species. Since Applicants did not traverse the restriction/election requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). Therefore, claims 4 and 16-17 are withdrawn from further consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03. Applicants preserve their right to file a divisional on the non-elected subject matter.
Status of the claims
Claims 1-3, 5, 7-9, 12-15,18-19, 26-28 and 82-84 are examined on merits in this office action.
Claim Rejections – Improper Markush Grouping
Claims 1-3, 5, 7-9, 12-15,18-19, 26-27 and 82-84 are rejected on the judicially-created basis that they contain 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 lack the required combination of a shared substantial structural feature and a common use that flows from that shared substantial structural feature for the following reasons: the claims encompass a sufficient number and variety of compound composition represented by structurally and functionally distinct compounds encompassed by combination of variety of groups represented by each of G, B, K, W, L1, L2 and A of formula (I). Each of the G, B, K, W, L1, L2 and A of formula (I) encompasses structurally and functionally divergent compounds/groups with no substantial structural elements in common and their combination as claimed encompasses inordinately a large number of structurally divergent compounds which also does not provide a shared substantial structural feature having a defined property and a common use that flows from the shared substantial structural feature. The cleavable linker of the probe as claimed comprises an A portion comprising a cleavage site, an L1 portion at a proximal region of the cleavable linker and an L2 portion at a distal region of the cleavable linker. The L1 portion and L2 portion have not been clearly defined in claim 1 or in the specification and thus includes various divergent groups/compounds not only limited to the claimed formula (I-1) and (I-2) of claims 26 and 27 and each of L1 and L2 encompass distinct structure that do not provide a shared substantial structural feature. The A portion as claimed encompasses various cleavage site, including sites cleavable by various types of enzymes, various types of compounds and conditions. As for example, the cleavage site may encompass a peptide sequence cleavable by various enzyme, a sugar-based linker may comprise sites cleavable by galactosidase, a linker cleavable by chemical cleavage such as acid labile cleavage site, oxidative cleavage site or a reductive cleavage site, each having distinct linker structures and which does not provide a shared substantial structural feature. As for example, a cleavable linker having an azobenzene derivative (
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), does not have any common substantial structural feature with a cleavable linker having a Dde derivative (
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) or with a cleavable peptide wherein each cleavable, as for example human rhinovirus 3C(HRV3C) protease recognition sequence or tobacovirus recognition sequence to exemplify a few. The tag as claimed, and as disclosed in the specification (paragraphs [0024], [0025] and [0091]) includes various distinct structures with distinct functions, as for example, an azide is structurally and functionally distinct from a biotin or digoxigenin tag or a halo tag and they do not provide a shared substantial structural feature. Similarly, the W (light activated warhead; paragraphs [0010], [0011]) , K (crosslinkable group; [0016]) and G (a bait molecule, paragraph [0062-0069], [0107]) as disclosed in recited paragraphs, each encompass large number of distinct compounds with distinct structure, which do not share any substantial structural feature. Therefore, the combination of the structurally divergent structure encompassed by each of G, B, K, W, L1, L2 and A, the formula (I) encompasses an inordinately a large number of structurally divergent compounds which do not have a shared substantial structural feature and a common use that flows from that shared substantial structural feature.
In response to this rejection, Applicants should either amend the claims to recite only individual species or a 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 do 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).
Claim Rejections - 35 USC § 112
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, 26, 27 and claim 2-3, 5, 7-9, 12-15,18-19 and 82-84 being dependent thereon, 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 “L1 portion at a proximal region of the cleavable linker” and “L2 portion at a distal region of the cleavable linker”. Claim 26 and 27 recites “proximal end of A portion” and “distal end of A portion”.
The terms proximal region and distal region with respect to cleavable linker and A portion have not been clearly defined or described in the specification and thus is it unclear what side of the cleavable linker is intended to refer by proximal region and what side of region of the cleavable linker is intended for distal region. Further it is unclear what side of A portion in claim 1 is intended for proximal and distal end. Proximal means closure and distal means further away and it is unclear what is intended to refer by proximal region of cleavable linker? Proximal/closure to what? A portion? If this is with respect to A portion, then it is unclear what is intended to refer by “proximal end of the A portion” and “distal end of A portion” recited in claims 26 and 27.
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 1-3, 5, 7-9, 12-15,18-19, 26-27 and 82-84 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit noted the importance of an application's disclosure and stated, “the hallmark of written description is disclosure.” A disclosure adequately describes an invention when it “reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Id. at 1351. “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs, 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). The Federal Circuit explained what is required to meet the written description requirement in Ariad Pharm., Inc. v. Eli Lilly & Co.:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357-58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359.
A written description of a chemical genus “requires a precise definition, such as by structure, formula, [or] chemical name” of the claimed subject matter sufficient to distinguish it from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed. Cir. 1997). The Federal Circuit reflected on Eli Lilly in Ariad while explaining how to sufficiently describe of a genus of compounds:
We held that a sufficient description of a genus instead requires the disclosure of
either a representative number of species falling within the scope of the genus or
structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
A "representative number of species" must typify the entire claimed genus and account for variation between the species of the genus. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014)
[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004).
The present claims encompass a genus of compounds represented by formula (I) wherein each of G, B, K, W, L1, L2 and A of formula (I) encompasses structurally and functionally divergent compounds/groups with no substantial structural elements in common and their combination as claimed encompasses inordinately a large number of structurally divergent compounds. The cleavable linker of the probe as claimed comprises an A portion comprising a cleavage site, an L1 portion at a proximal region of the cleavable linker and an L2 portion at a distal region of the cleavable linker. The L1 portion and L2 portion have not been clearly defined in claim 1 or in the specification and thus includes various divergent groups/compounds not only limited to the claimed formula (I-1) and (I-2) of claims 26 and 27 and each of L1 and L2 encompass distinct structure that do not provide a shared substantial structural feature. The A portion as claimed encompasses various cleavage site, including sites cleavable by various types of enzymes, various types of compounds and conditions. As for example, the cleavage site may encompass a peptide sequence cleavable by various enzyme, a sugar-based linker may comprise sites cleavable by galactosidase, a linker cleavable by chemical cleavage such as acid labile cleavage site, oxidative cleavage site or a reductive cleavage site, each having distinct linker structures. As for example, a cleavable linker having an azobenzene derivative (
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), does not have any common substantial structural feature with a cleavable linker having a Dde derivative (
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) or with a cleavable peptide wherein each cleavable, as for example human rhinovirus 3C(HRV3C) protease recognition sequence or tobacovirus recognition sequence, to exemplify a few. The tag as claimed, and as disclosed in the specification (paragraphs [0024], [0025] and [0091]) includes various distinct structures with distinct functions, as for example, an azide is structurally and functionally distinct from a biotin or digoxigenin tag or a halo tag and they do not provide a shared substantial structural feature. Similarly, the W (light activated warhead; paragraphs [0010], [0011]) , K (crosslinkable group; [0016]) and G (a bait molecule, paragraph [0062-0069], [0107]) as disclosed in recited paragraphs, each encompass large number of distinct compounds with distinct structure. Therefore, the combination of the structurally divergent structure encompassed by each of G, B, K, W, L1, L2 and A, the formula (I) encompasses an inordinately a large number of structurally divergent compounds for which the specification does not have a disclosure of representative species that represents the entire genus of divergent compounds represented by the combination of divergent groups represented by each of G, B, K, W, L1, L2 and A, the formula (I) as described above.
This genus encompasses an untenable number of compounds, due to the number of possible permutations based on all of the combinations of the variables G, B, K, W, L1, L2 and A contained in the genus. The number of compounds embraced by this genus found in claims may be roughly determined by cumulatively multiplying the number of possibilities, n, for each variable:
The number of compounds embraced by this genus of formula (I) compound of claim 1 may be roughly determined by cumulatively multiplying the number of possibilities, n, for each variable
(# bait molecule G permutations) × (# of L2 portion permutation) x (# of cleavage site A permutation) x (# of L1 portion permutation) x (# of tag B permutation) x (# cross-linkable group K permutations) x (# light activated warhead W permutation) = Total compounds encompassed
Conservatively speaking, the “photoreactive and cleavable probe” represents an innumerable number of possible substituents because of the open-ended definition of L1 and L2 and some with the definition for G, A, B, K and W.
By contrast, the specification supports this massive genus with only few species disclosed in paragraphs [0245], [0257] and [0260], wherein in all the species the the cleavable linker is limited to peptide sequence having an enzyme cleavable site, the tag is limited to biotin, the warhead is limited to benzophenone, the cross-linkable moiety is limited to limited to click chemistry-based moiety and the bait is limited to antibody.
These few species cannot possibly typify the entire genus claimed or account for all of the variation between species of such a large genus. For example, support for the entirety of the claimed genus cannot be extrapolated from the few disclosed species, because the genus encompasses an untenable number of compounds generated by variables L1, L2, G, A, B, K and W, each of which encompasses structurally and functionally distinct compounds.
Chemistry is generally considered to be unpredictable and/or have unpredictable factors. See, e.g.,In re Carleton, 599 F.2d 1021, 202 USPQ 165, 170 (CCPA 1979) ("Although there is a vast amount of knowledge about general relationships in the chemical arts, chemistry is still largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave.”). The pharmaceutical art, that is the use of a chemical compound to affect a desired physiological activity, is generally considered to be unpredictable and/or have unpredictable factors. See, e.g., In re Fisher, 427 F.2d 833, 839 (CCPA 1970) (“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved (emphasis added); In re Bowden, 183 F.2d 115, 86 USPQ 419, 423 (“chemical reactions frequently are unpredictable”).
Considering the unpredictability found in organic synthesis, exchanging even one substituent for another cannot be considered a foregone conclusion. Accordingly, when a claim presents a genus with substantial variation as that currently presented by Applicant, the disclosure must adequately reflect such variation with a representative number of species. The lack of any disclosure of examples may be considered in determining whether a claimed invention was adequately described. Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011).
Disclosure of only a few of the species are not a “representative number of species” for an unpredictable art such as a chemical reaction. See, e.g., Ariad, 598 F.3d at 1354-55 (claiming that the inventor has an obligation to disclose examples when the art is unpredictable). The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the entirety of the genus now claimed, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the entirety of the claimed genus.
Applicant may overcome this rejection by limiting the scope of the claimed genus in accord with the claimed species, taking connectivity into account.
Allowable Subject Matter
Claim 1 will be allowable if limited to the elected species. Elected species of multifunctional photoreactive probe are free of prior arts. Claim 28 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Miyajima et al (ACS Chem. Biol. 2020), discloses tetrafunctional probes comprising a biotin (Tag B), a 2-aryl-5-carboxytetrazole or diazirine (as a photo reactive group/a light activated group; W), a hydrazine labile Dde cleavable linker; A), and a ligand of interest (i.e. bait or G) (abstract and Fig.1). However, Miyajima does not teach or reasonably suggest a tetrafunctional probe further comprising a cross-linkable group in the arrangement as claimed in claim 1 and does not suggest a kit further comprising a connector molecule comprising a warhead binding region and a cross-linkable moiety wherein the warhead binding region preferentially binds the warhead (photoreactive group) and the cross-linkable group of the connector molecule preferentially binds to the probe cross-linkable moiety.
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678