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 .
DETAILED ACTION
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 Group II, claims 5-13, in response to restriction requirement of 9/8/25 is acknowledged. Applicant’s election of the followings in response to election of species requirement is also acknowledged:
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. Applicant stated that claims 5-13 read on the elected species.
Therefore, claims 1-4 are withdrawn from further consideration as being directed to a non-elected invention.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 5-13 are examined on merits in this office action.
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 5-13 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 5 is directed to a method for detecting a target moiety in a sample and recites “Y: antigen recognizing moiety” for the conjugate utilizing in the detection process. The recitation “Y: antigen recognizing moiety” does not provide any indication or certainty that the antigen recognition moiety specifically binds the target moiety in the sample and thus it is unclear how is the target moiety in the sample is being detected with the method process utilizing the conjugate of formula (I).
Claim 6 recites “by enzymatically degrading the first and second spacers P1 and P2, the antigen recognizing moiety, Y is cleaved from the target moiety”. The claim is confusing because claim 5, step d) recites “degrading spacer P1 and/or second P2”. The “and/or” encompass both P1 and P2 or either one of P1 or P2 but however, claim 6 recites degrading first and second spacer P2. Since claim 6 is not a positive recitation (..by enzymatically degrading ….), it is unclear as to whether the claim is intended to limit claim 5 with the process of degradation step d) with degradation of both P1 and P2? Further, it is unclear how is the Y is cleaved from the target moiety by this process? The conjugate binds to target moiety via the Y target recognition moiety that specifically binds the target moiety. By cleaving/degrading the P1, P2 and X, Y would be released from P1, P2 and X, not the linkage/bond of Y from the target moiety as there is not steps provided in claim 5 to release/dissociate Y from the target moiety.
Claims 8-13 recites “degradable spacers P”, for which the claims lack an antecedent basis. Each of the claims is separately dependent on claim 5, which does not recite “P” in the conjugate of formula (I). Thus it is unclear what spacers are intended to refer by “P” in the claims.
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 5-13 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. Claim 5 is directed to a method of detecting a target moiety in a sample utilizing a conjugate of general formula (I) Yn – P1(P2 – Xm)0.
As claimed, the first enzymatically degradable spacer P1 and the second degradable spacer P2 encompasses an inordinately a large number of structurally and functionally distinct compounds. Specification teaches that the enzymatically degradable spacer P1 and P2 can be any molecules that can be cleaved by a specific enzyme. Specification teaches suitable spacers (which is not limited to the exemplified spacers), for example, include polysaccharides, proteins, peptides, depsipeptides, polyesters, nucleic acids, and derivatives thereof and suitable polysaccharides (which is not limited to the suitable ones only) include dextrans, pullulans, inulins, amylose, cellulose, hemicelluloses, such as xylan or glucomannan, pectin, chitosan, or chitin. Each or the spacers are structurally divergent. As for example, a protein spacer with various distinct enzyme cleavable site is structurally, functionally distinct from a dextran spacer, which does not have a structural similarity and a substantial common structural feature. As claimed, Y-P1(P2-X) of the conjugate, as claimed, may comprise a protein insulin linked to a insulin-like growth factor 1 (IGF-1), wherein the insulin is linked to an antibody and the IGF-1 is linked to a detection moiety and wherein the insulin is degradable by DPP-4 and the IGF-1 is degradable by cathepsin. This is just one example of the diversity of claimed conjugate encompassed by proteins, let alone the diversity provides by the various polysaccharides, various, nucleic acids, polyesters and their derivatives. Thus, as claimed, with the various structurally and functionally divergent spacers in the conjugate of formula (I), the formula encompass an inordinately a large number of structurally and functionally divergent structure without any substantial common structural feature for which the specification does not have a clear descriptive support.
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.
[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).
MPEP § 2163 further states that, for a claimed genus, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus:
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, 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) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[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.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Emphasis added.
Throughout the specification, the only example and the only structure for a conjugate disclosed is described in paragraphs [0072]-[0080], wherein the first enzymatically degradable spacer is strictly limited to “Dextran” degradable by enzyme dextranase and the second enzymatically degradable spacer is strictly limited to short ssDNA hybridized to complementary dye-modified oligos that is capable of DNase mediated degradation of the DNA. While the encompassed spacers P1 and P2 and structurally and functionally divergent and which each encompasses degrading an enormous number of different enzymes, the disclosure of only a single construct with a single species of dextran spacer for P1 and single species of DNA spacer for P2, does not provide representative species for the inordinately a large number of distinct enzyme cleavable spacers for the conjugate of general formula (I) as encompassed by claim 5.
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 single species of a conjugate cannot be considered as a disclosure of 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
Claims 5-13 are rejected under 35 U.S.C. 103 as obvious over Dose et al. (WO 2020/216439A1; cited in IDS of 10/31/2022) in view of Levengood (US 2020/0129639A1).
In regards to claims 5-6 and 8-12, Dose teaches detecting a target moiety in a sample comprising:
a) providing at least one conjugate having the general formula I
(I) (Xo-L)n - P - Ym
with Y : antigen recognizing moiety recognizing the target moiety,
P : enzymatically degradable spacer,
X : fluorescent moiety,
L : linker unit comprising one or more polyethyleneglycol residues n, m : integer between 1 and 100,
o: integer between 1 and 100
wherein L covalently bounds the fluorescent moiety X and the enzymatically degradable spacer P and Y is covalently bound to the enzymatically degradable spacer P.
b) contacting the sample of biological specimens with the conjugate according to formula (I), thereby labeling the target moiety recognized by the antigen recognizing moiety Y
c) detecting the target moiety labelled with the conjugate with the fluorescent moiety X, and
d) degrading the enzymatically degradable spacer P is degraded by an enzyme, thereby cleaving the fluorescent moieties X from the labelled target moiety (see claims 7 and 8 of the reference).
Dose teaches that the P comprises multivalent linker dextran (para [0020], [0047], [00126]) among others and are degradable by enzyme dextranases (claim 10). Dose teaches linking plurality of dyes to aminodextran para [00124-00127]). Dose also teaches plurality of specific binding substance conjugated to the multivalent linker dextran (para [00129] and claim 1, m=1-100). Dose teaches that in step a) of the method, at least one conjugate with the general formula (I) is provided. In order to detect different target moieties or the same target moiety by different detection moieties, different conjugates having the general formula (I) can be provided, wherein the conjugates and its components, Y, P, L, X,o, n, m, have the same meaning, but can be the same or different kind and/or amount of antigen recognizing moiety Y and/or linker unit L and/or enzymatically degradable spacer P and/or fluorescent moiety X.
Dose teaches the linker/spacer L comprises polyethylene glycol residues but however, does not teach L is a cleavable/degradable linker.
Levengood teaches multi-drug antibody conjugates comprising multivalent linker conjugated to an antibody and to plurality of drug units (claims 1, 10, 28) wherein the drug unis may be different (Claim 1, para [0009], [0032], [0069], [0205]). Levengood teaches that the linker L may comprise releasable linker wherein the releasable linker may be conditionally releasable linker releasable by enzymes (paragraphs [0150], [0159-0161], [0162], [0169], [0170]).
Therefore, given the fact that multivalent linker may be utilized for conjugating plurality of different units through releasable linker including conditionally releasable enzyme cleavable linkers, it would be obvious to one of ordinary skilled in the art to easily envisage considering the linkers L of Dose having conditionally cleavable moiety with the expectation of providing versatility of the conjugate of Dose having different dyes with different enzyme cleavable linker for tuning and removing with ease with a reasonable expectation of success. Since Dose teaches multiplexing for detection of different target moieties or the same target moiety by different detection moieties, wherein the conjugates and its components, Y, P, L, X,o, n, m, have the same meaning, but can be the same or different kind and/or amount of antigen recognizing moiety Y and/or linker unit L and/or enzymatically degradable spacer P and/or fluorescent moiety X, one of ordinary skilled in the art can easily envisage different enzymatically cleavable linker for L in the conjugate of Dose in view of Levengood for controlled release and detection of different fluorescent moiety by controlled release with a reasonable expectation of success.
In regards to claim 7, as described above, Dose teaches dextran for multivalent spacer P and also teaches enzyme dextranase that degrades the dextran spacer (paragraphs [00124-00128] and [00132]).
In regards to claim 13, Dose teaches that the method may use a variety of combinations of conjugates. For example, a conjugate may comprise antibodies specific for two different epitopes, like two different anti-CD34 antibodies. Different antigens may be addressed with different conjugates comprising different antibodies, for example, anti-CD4 and anti-CD8 for differentiation between two distinct T-cell-populations or anti-CD4 and anti-CD25 for determination of different cell subpopulations like regulatory T-cells (para [0074]). In view of Levengood, one of ordinary skilled in the art would easily envisage including different fluorescent moieties with different conditionally cleavable linker L with the expectation of expanding arsenal of the conjugate with conjugates having versatility of multiplex detection with controlled released of fluorescent moieties for detection of various cells with reasonable expectation of success.
Conclusion
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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