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 .
Acknowledgement of Receipt
Applicant’s Response, filed 1/29/2026, in reply to the Office Action mailed 10/29/2026, is acknowledged and has been entered. Claims 1, 3, 5 and 41 have been amended. Claims 1-3, 5, 8, 9, 11, 30, 39-42, 45, 47, 49-52, 54-57, 66-69 and 78 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments and the Declaration of Inventor Majonis have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
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.
Claim(s) 1-3, 5-9, 11, 30, 39-42, 45, 47, 49-52, 54-57, 66-69 and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Winnik et al. (US 2008/0003616) in view of Perez (US 2020/0023086) for reasons set forth in the previous Office Action.
Response to Arguments
Applicant argues DFO, DOTA, and DTPA are functionally different chelators such that it would not have been obvious to one of ordinary skill in the art to use DFO in the polymers of Winnik. Applicant further respectfully submits that even if Perez suggests DFO, DOTA, and DTPA are functionally equivalent for a use described in Perez (which Applicant does not admit), a person of ordinary skill in the art would not extrapolate that teaching to assume that DFO, DOTA, and DTPA would be functionally equivalent for the use described in Winnik. Applicant argues that Winnik discloses novel metal-polymer conjugates for ICP-MS-based flow cytometry.. and further teaches that the "selection criteria" for identifying an appropriate ligand includes "heptadentate or octadentate coordination to promote kinetic stability against metal ion dissociation. Applicant contends that the polymers of Winnik are well-defined metal-chelating polymers that remain well-dispersed in solution with a very small radius of gyration. In comparison to Winnik, Perez teaches polymer nanoparticles that are intended for a different type of imaging analysis, that serve a different purpose, and that are much larger in size. Applicant asserts that Perez teaches a variety of ligands including those that do not fall within the "selection criteria" defined by Winnik. Critically, DFO is a hexadentate ligand, which does not fall within the ligand "selection criteria" defined by Winnik. In Winnik's method of elemental analysis by ICP-MS, the polymers for analysis must be well-defined and well-dispersed without aggregation. Majonis Decl. I 4. Avoiding aggregation of the polymers is important and requires using an optimal chelator for each particular element, and Winnik identifies specific selection criteria for the chelators. Id. By contrast, in Perez the mechanism of nanoparticle formation relies on aggregation. Id. 1 5. Thus, Perez need not be concerned with identifying optimal chelators, and a wider range of chelators is useful with the nanoparticles and methods of Perez. Id.
Applicant’s arguments have been fully considered but are not found to be persuasive. See MPEP 2123, directed to rejection over prior art’s broad disclosure instead of preferred embodiments. Patents are relevant as prior ar art for all they contain. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). In the instant case, while the Examples are directed to DOTA or DTPA as chelators (paragraph 0096-98), Winnik is generally directed to polydentate chelators that may chelate the metal ion (paragraph 0036). Winnik further teaches that the examples are exemplary and are not intended to limit the scope of the invention (paragraph 0095). With regard to arguments directed to particle size, it is respectfully submitted that the Perez reference is relied upon for metal chelators, not the polymer itself.
Applicant further argues that Perez teaches a variety of imaging compounds, including superparamagnetic compounds with metals, superparamagnetic compounds with metal oxides, radionuclides, and X-ray/CT imaging compounds, and that Perez only teaches chelators for the radionuclides, which are excluded from independent claims 1 and 78. Applicant further references the Declaration of Inventor Majonis and states that while Perez lists many different types of imaging compounds and many different chelators, there is no teaching that the chelators are equivalently useful for any particular imaging compounds. Critically, the chelators in paragraph [0052] include DOTA and DTPA but do not include DFO. Paragraph [0052] fails to mention DFO, SO paragraph [0052] cannot teach the purported functional equivalence. At paragraph [0058] Perez again teaches multiple imaging compounds and chelators, with the general term "X-ray or PET detectable compound" applying to many different metal elements. Applicant asserts that Perez teaches that there are "aspects" of the invention in which DFO is useful and there are other "aspects" of the invention where DOTA or DTPA is useful, but Perez fails to teach whether they are useful in the same "aspects" or useful with the same imaging compound and that there is no teaching that the chelators are equivalently useful, citing the Declaration. Applicant asserts that Dr. Majonis confirms that a person of ordinary skill in the art would not interpret Perez, to teach functional utility of any chelators. Dr. Majonis also explains that ligands for the Winnik polymers and methods have more rigorous requirements than ligands for the Perez nanoparticles, at least with regard to preventing aggregation. Accordingly, Applicant respectfully submits that Perez fails to teach or suggest that DFO, DOTA, and DTPA are functionally equivalent chelators. Because Winnik and Perez disclose different types of imaging with different types of polymers where optimization of the chelator is significantly more important in Winnik than in Perez, a person of ordinary skill in the art would not interpret Perez to teach or suggest that DFO, DOTA, and DTPA would be functionally equivalent for the use described in Winnik.
Applicant’s arguments and the Declaration of Inventor Majonis have been fully considered. With regard to the argument that ligands for the Winnik polymers and methods have more rigorous requirements than ligands for the Perez nanoparticles and that chelators are not equivalently useful for any particular imaging compounds, it is respectfully submitted that Winnik is generally directed to polydentate chelators that may chelate the metal ion (paragraph 0036). Winnik further teaches that the examples are exemplary and are not intended to limit the scope of the invention (paragraph 0095), as such one of ordinary skill in the art could have readily substituted another chelator which accomplishes the function of chelating a metal ion, including those set forth in paragraph 0037 of Winnik of atomic number 21-30, 39-48, 57-80 and 89-92, as overlapping with metal ions set forth in Perez, including e.g. zirconium. Further it is noted that the arguments and Declaration are not commensurate in scope with the claims, as the claims are not limited to DFO, rather include any azamacrocycle, cyclam, salophen, etc. ligands as well.
New Grounds for Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
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.
Claim(s) 1-3, 5-9, 11, 30, 39-42, 45, 47, 49-52, 54-57, 66-69 and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Winnik et al. (US 2008/0003616) in view of Jakubowski (DE 102012104504).
Winnik teaches element tags based on novel metal-polymer conjugates are provided for elemental analysis of analytes, including ICP-MS. A polymer backbone is functionalized to irreversibly bind metals that are selected prior to use by the user. The polymer is further functionalized to attach a linker which allows for attachment to antibodies or other affinity reagents. The polymer format allows attachment of many copies of a given isotope, which linearly improves sensitivity. The metal-polymer conjugate tags enable multiplexed assay in two formats: bulk assay, where the average biomarker distribution in the sample is diagnostic, and single cell format to distinguish a rare (for example a diseased) cell in a complex sample (for example, blood) (abstract).
An aspect of the invention is to provide an element tag comprising a polymer, wherein the polymer comprises at least one metal-binding pendant group that comprises at least one metal atom or is capable of binding at least one metal atom. The element tag can further comprise a functional group that allows the polymer to be attached to one of a linker, a spacer, or a biomolecule. The element tag can be water soluble. It can also be negatively charged. The number of metal-binding pendant groups capable of binding at least one metal atom can be between approximately 1 and 1000, and most typically between approximately 10 and 250. At least one metal atom can be bound to at least one of the metal-binding pendant groups. The polymer can have a degree of polymerization of between approximately 1 and 1000, and most typically between 10 and 250 (paragraph 0045).
The metal-binding pendant group can be attached to the polymer through an ester or through an amide. The functional group can be a thiol-reactive group. The metal atom can be a transition element or an isotope thereof, or a lanthanide or an isotope of a lanthanide. The element tag can further comprise a linker attached to the functional group of the polymer, wherein the linker is capable of covalent attachment to a biomolecule. The element tag can further comprise a spacer attached to the linker, wherein the spacer is capable of attachment to a biomolecule. The spacer can be a polyethylene glycol (PEG) spacer. The spacer can comprise a functional group that is capable of binding the spacer to the polymer via a spacer-reactive functional group on the polymer. Further the spacer can contain a functional group that is capable of binding a linker to the spacer (paragraph 0047).
Transition element includes those having atomic number 21-30, 39-48, 57-80 and 89-92 (paragraph 0037).
Regarding claims 3, 6, 7 and 57, the metal-binding pendant group that is capable of binding at least one metal atom can comprise a diethylenetriaminepentaacetate (DTPA) ligand or a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand. The method can further comprise functionalizing the polymer, wherein the functional group is capable of covalently binding a biomolecule. The method can further comprise attaching a linker to the functional group of the polymer, wherein the linker is capable of binding a biomolecule. The method can further comprise covalently binding a biomolecule to the linker. Finally, the method can further comprise binding at least one metal atom to at least one metal-binding pendant group (paragraph 0050). Regarding claim
Schematic views of attaching ligands (pending groups) to polymers produced by anionic polymerization are shown in Scheme 5 and PDMAEMA, Scheme 6. See also Scheme 5, directed to a route for attaching (L) to the polymer which involves reacting the tetrabutylammonium carboxylate salt of the polymer with the bromoacetamide derivative of (L)-NH2 (Scheme 5, FIG. 4), which are interpreted to include soluble groups (i.e. the chelate itself, amine/amide, etc.).
Specifically designed for elemental analysis, such a tag would typically be: (i) water soluble, (ii) non-toxic, (iii) easily separated from a tagged material by known chromatographic, centrifugation, filtration or dialysis methods; and, in addition, can have three or four moieties: the attachment group (linker), possibly a spacer (for example, a PEG spacer), the polymer skeleton (carrier), and the tag atoms (as many tag atoms (of the same metal or isotope, or of a different metal and/or isotope) as possible). For different elemental analyzers the characteristics of the element tag can be similar (paragraph 0090).
An important aspect of the invention is the synthesis of a polymer, to which a large number of tag atoms can be attached. Typically the tag atoms are metal atoms. The polymer can be water soluble This moiety is not limited by chemical content. However, it simplifies analysis if the skeleton has a relatively reproducible size (for example, length, number of tag atoms, reproducible dendrimer character, etc.). The requirements for stability, solubility, and non-toxicity are also taken into consideration. Thus, the preparation and characterization of a functional water-soluble polymer by a synthetic strategy that places many functional groups along the backbone plus a different group at one end that can be used to attach the polymer via a linker to a biomolecule (for example, an affinity reagent) is part of this invention (paragraph 0092).
Regarding claims 9 and 11, the polymers may include a spacer attached to a linker, wherein the spacer is capable of attachment to a biomolecule. The spacer can be a polyethylene glycol (PEG) spacer, which is considered to be pendant from the polymer, consistent with the instant claims. See also paragraph 0106, directed to end-group control and coupling chemistry, an end group is pendant from the polymer backbone.
Regarding claim 30, polymers are lyophilized, see Example 4.
Regarding claims 49-51, for example a PEG2000 (2 KDa) has a mean degree of polymerization of 45 corresponding to 140 backbone atoms, and PEG5000 has 340 backbone atoms (paragraph 0093).
Regarding claims 55-6, coupling to affinity reagent / antibody is taught paragraph 0106, 0110+).
Regarding claims 66 and 67, the polymers may be amenable to synthesis by a route that leads to a relatively narrow polydispersity. The polymer may be synthesized by atom transfer radical polymerization (ATRP) or reversible addition-fragmentation (RAFT) polymerization, which should lead to values of Mw/Mn in the range of 1.1 to 1.2 (paragraph 0094).
Regarding claims 68 and 69, the polymer typically contains between 10 and 250 pendant metal binding groups (paragraph 0045).
Accordingly, Winnik teaches a polymer comprising pendant groups that chelate zirconium and/or hafnium, wherein at least one of the pendant groups comprises a chelator and a solubility assisting group. Winnik does not specifically recite an azamacrocycle which is not DOTA or DFO as a chelator.
Jakubowski teaches biomolecule labeling and relates to the use of peptides to label biomolecules having hetero elements, including atomic spectroscopic analysis (abstract, page 1 translation). A marker substance having a reactive group is taught, wherein the marker substance is adapted for the specific detection of biomaterial and a support material containing at least two pieces of a subunit linked together by a peptide bond, wherein the subunit comprises at least one amino acid with a heteroelement-containing reporter group, and the heteroelement is any chemical element other than hydrogen (H), carbon (C), nitrogen (N) and oxygen (O). The marker substance of claim 1, wherein the subunit is a peptide. A marker substance according to claim 1 or 2, wherein the heteroelement is selected from: lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), silver (Ag), aluminum (Al), arsenic (As), gold (Au), beryllium (Be), bismuth (Bi), cadmium (Cd), germanium (Ge), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), gallium (Ga), mercury (Hg), indium (In), lithium (Li), manganese (Mn), sodium (Na), lead (Pb), rubidium (Rb), antimony (Sb), scandium (Sc), selenium (Se), tin (Sn), tellurium (Tl), vanadium (V), tungsten (W), yttrium (Y), zinc (Zn), zirconium (Zr), sulfur (S), phosphorus (P), silicon (Si), iodine (I), bromine (Br), fluorine (F). A marker substance is claimed according to one of claims 1 to 3, wherein the reporter group comprises a chelating agent, a complexing agent and / or an ion exchanger. A marker substance according to claim 4, is claimed wherein the chelating agent and / or complexing agent is selected from: cyclohexanediaminetetraacetic acid (CDTA); Diethylenetriamine pentaacetic acid (DTPA); Ethylenediaminetetraacetic acid (EDTA); Ethylene glycol bis (aminoethyl ether) -N, N, N ', N'-tetraacetic acid (EGTA); Nitrilotriacetic acid (NTA); N- (2-hydroxyethyl) ethylenediamine-N, N, N'-triacetic acid (HEDTA); Triethylenetetraminehexaacetic acid (TTHA); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA); a NOTA derivative; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); Diethylenetriamine-N, N ', N "-triacetic acid-N, N" -bis (2-methylpyridine) (DTPA-BP); Diethylenetriamine-N, N ', N "-triacetic acid-N, N" -bis (methylamide) (DTPA-BMA); 1-oxa-4,7,10-tetraazacyclododecane-4,7,10-triacetic acid (DO3A); a DO3A derivative; Diethylenetriamine-N, N, N ', N ", N" -pentaacetic acid (DTPAA); p-isothiocyanatobenzyl-desferrioxamine (Df-Bn-NCS); 1,4,7,10,13,16,19,22-octaazacyclotetracosane-1,4,7,10,13,16,19,22-octacetic acid (OTEC); 1,4,7,10,14,17,20,23-octaazacyclohexacosane-1,4,7,10,14,17,20,23-octacetic acid (OHEC); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra (methylene phosphonate) (DOTP); benzyloxypropionictetraacetate (BOPTA); calixarene; cryptate; trispyridine europium cryptate (TBP cryptate); 1,4,8,11-tetraazacyclotetradecane (cyclam); 1,4,7,10-tetraazacyclododecane (cyclen); 1,4,7-triazacyclononane (tacn), or among carbonyl complexes, carbene complexes and metallocene-based reagents. See claims 1-5. The reporter may be used in qualitative and / or quantitative detection of an analyte in a sample, comprising: (a) labeling an analyte with a detection reagent according to claim 19; and (b) analysis by mass spectrometry and / or atomic spectroscopy, see claim 20.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide an isotope of zirconium or hafnium as the transition element bound to a metal-binding pendant group attached to a polymer backbone taught by Winnik. One would have been motivated to do so because Winnik teaches that transition elements of atomic number 39-48, 57-80, which encompass the atomic numbers of zirconium and hafnium. One of ordinary skill in the art would have been capable of selection from among the limited number of metals with a reasonable expectation of success because Winnik teaches such metals to be suitable for use in elemental analysis of analytes.
It would have been further obvious to one of ordinary skill in the art at the time of the invention to substitute another azamacrocycle or DFO as a functionally equivalent chelator to DOTA or DTPA on the polymeric backbone having at least one metal-binding pendant group taught by Winnik when the teaching of Winnik is taken in view of Jakubowski. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known chelator for another, and the results of the substitution would have been predictable, that is chelation of a metal ion/ heteroelement such as zirconium (Zr), by a chelator as a marker for use as a detection reagent for analysis by mass spectrometry and / or atomic spectroscopy.
With regard to claim 52, it would have been obvious to optimize the number of chelates and PEG groups as a matter of routine optimization of the polymer bearing pendant metal chelating ligands and/or PEG spacer/linker groups, for example variation in metal binding groups is taught, paragraph 0045. Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Conclusion
No claims are allowed at this time.
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 LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights