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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/17/2025 has been entered.
Status of Claims
Claims 1, 3 and 5-13 are currently pending. Claims 8 and 11 are withdrawn. Claims 1, 3, 5-7, 9, 10, 12 and 13 are under examination.
Withdrawn Objections/Rejections
In light new sequence listing dated 12/17/2025 with no errors found, the objection is hereby withdrawn.
In light of amended specification filed 12/17/2025, the objection to the specification is hereby withdrawn.
In light of amendments and Affidavit filed 12/17/2025, the 35 U.S.C. 112(a) rejection is hereby withdrawn.
In light of amendments, the 35 U.S.C. 112(b) rejection in the previous office action is hereby withdrawn.
In light of amendments, the 35 U.S.C. 103 rejection in the previous office action is hereby withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 112 that form the basis for the rejections under this section made in this Office action.
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 12 and 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.
With respect to claims 12-13, the claims are unclear to the boundary of the chemical structure of each multi-armed polyethylene glycol polymer because claim 1 recites each multi-armed PEG polymer comprises four arms with each arm being conjugated to an individual fluorescent label or comprises eight arms with each arm being conjugated to an individual fluorescent label (i.e., either 4 or 8 fluorescent labels for each PEG polymer). However, in claims 12-13 the ranges of fluorescent labels are from 4-20 or 4-10, which would contain a wider range of PEG arms to compensate for the additional fluorescent labels or other chemical structures are also attaching to additional fluorescent labels in a manner that is not specified in the claims. The claims are unclear to the ranges of fluorescent labels when there is only either 4 or 8 arms for fluorescent label attachments.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 12-13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The claims recite limitations of range of 4-20 and 4-10 of individual fluorescent labels do not further limit the claimed PEG polymer. For example, 8-armed PEG polymer as claimed requires 8 fluorescent labels but these claims recite limitations that only require 4, 5, 6 fluorescent labels.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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.
Claims 1, 3, 5-7, 9, 10, 12 and 13 are rejected under 35 U.S.C. 103 as obvious over Dose (US2016/0347907A1, Application No. 14/723,505 was filed on 05/28/2015 (PTO-892 dated 05/08/2025), in view of Kotagiri et al. (“Antibody Quantum Dot Conjugates Developed via Copper-Free Click Chemistry for Rapid Analysis of Biological Samples Using a Microfluidic Microsphere Array System” Bioconjugate Chemistry, vol. 25, pgs. 1272-1281, published 06/09/2014), as evidenced by Creative PEGWorks, retrieved on 03/13/2026.
Dose teaches that fluorescent dyes such as multi-arm polyethylene glycols are highly fluorescent without noticeable quenching (at para. [0015]). Dose also teaches in the claims the structures of the fluorescent dye conjugate:
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Emphasis added.
Dose discloses in Example 1:
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As discussed above, Dose teaches using maleimide chemistry for conjugation an antibody with a branched PEG construct. Dose also teaches reactive groups R wherein the fluorescent dyes according to the invention are attached to biomolecules (i.e., antibody) via groups R, comprising a reactive group and Groups R shall be capable of forming covalent bonds via the reactive group of the biomolecule and the reactive groups may be active esters, maleimide, hydrazine, alkyne, or alkyl azide (at paras. [0049] and [0053]). Dose teaches the fluorophore F is cyanine dyes (at para. [0037]). Dose teaches the IgG antibody with 2 to 7 fluorescent polyether labels carrying each 4 to 6 fluorophore groups, resulting in fluorophore DOLs of 8 to 40 dye molecules per antibody molecule (at para. [0059]).
Dose does not exemplify the use of azide/alkyne chemistry, which is the elected species (a), a covalent attachment between an azide group of the antibody and a dibenzocyclooctyne (DIBO) group attached to a "20K8 PEG" linker as a mode of attachment of the fluorescent label to an antibody.
Kotagiri teaches an antibody-based technology for cancer diagnostic screening through quantum dot based fluoro-immunoconjugate (at abstract). Fig. 1 shows two reactions of an antibody with alkyne moiety through the reaction of the antibody with maleimide PEG DBCO or NHS PEG DBCO (dibenzocyclooctyne). Additionally, Fig. 1 shows an azide moiety conjugated to PEG spacer and through click reaction the antibody is covalently conjugated to the fluorescently labeled PEG polymer spacer. Kotagiri teaches employing click chemistry reaction through cycloaddition reactions and the rapid, specific, efficient, stable, facile, modular, and aqueous-phase conjugation strategy of click reaction has proven to be a reliable and powerful technique that is employed widely (at pg. 1273, left col., top of para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have conjugated together the multi-armed PEG polymer and antibody as taught by Dose through azide-alkyne cycloaddition reaction as taught by Kotagiri because (1) Dose already recognizes alkyne and azide as reactive groups for forming covalent bonds and discloses that a person will have no difficulty in selecting the appropriate chemistry with the reactive groups and (2) Kotagiri teaches that forming covalent bonds through azide-alkyne cyclcoaddition has proven to be a reliable and powerful technique that is widely employed for conjugation. Therefore, it would have been obvious to have employed the alkyne and azide reactive groups of Dose for cycloaddition reaction as taught by Kotagiri because the mechanism of cycloaddition reaction is selective between two recognized reactive groups in forming a reliable covalent bond that is widely employed and recognized. With respect to the elected species, it would have been obvious to the person to have attached azide with the antibody and dibenzocyclooctyne with the 8-Arm PEG of Dose because Kotagiri recognizes azide and dibenzocyclooctyne can be attached to individual PEG groups.
With respect to the functional recitation of fluorescent ratio, since the fluorescent dyes conjugated to the multi-armed polyethylene glyco polymers have the same structural elements as the instantly claimed fluorescently labeled multi-armed polyethylene glycol polymer, it would reasonably exhibit and possess the functional characteristics as claimed. In particular, Dose teaches the IgG antibody with 2 to 7 fluorescent polyether labels carrying each 4 to 6 fluorophore groups (at para. [0059]).
With respect to the limitation of the fluorescently labeled multi-armed PEG polymer with a MW greater than 10K Da, Creative PEGWorks has indicated that 8-Arm PEG has a MW 20K without fluorescent dyes. Additionally, Dose has recognized that the length of PEG is modifiable wherein n, m, or p is from 2 to 500 (see above). Meanwhile, the instant specification used PEG4 (see Tables). Because the range overlaps with the range disclosed by the prior art, a prima facie case of obviousness exists.
Meanwhile, Applicant is reminded that, according to MPEP § 2112.01 “Product and apparatus claims — when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent”, and a prima facie case of either anticipation or obviousness has been established:
“Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp.v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.).
See also In re Ludtke, 441 F.2d 660, 169 USPQ 563 (CCPA 1971) (Claim 1 was directed to a parachute canopy having concentric circumferential panels radially separated from each other by radially extending tie lines. The panels were separated “such that the critical velocity of each successively larger panel will be less than the critical velocity of the previous panel, whereby said parachute will sequentially open and thus gradually decelerate.” The court found that the claim was anticipated by Menget. Menget taught a parachute having three circumferential panels separated by tie lines. The court upheld the rejection finding that applicant had failed to show that Menget did not possess the functional characteristics of the claims.); Northam Warren Corp.v.D. F. Newfield Co., 7 F.Supp. 773, 22 USPQ 313 (E.D.N.Y. 1934) (A patent to a pencil for cleaning fingernails was held invalid because a pencil of the same structure for writing was found in the prior art.).” Emphasis in the original.
With respect to the elected species (a), Dose (at paras. [0007] and [0040]) teaches that it is particularly advantageous to use fluorescent dyes with sulfonate substituents, such as dyes of the Alexa fluor family provided by Thermo Fisher Scientific Inc. and that “The use of sulfonated dyes compared to unsulfonated dyes leads to even brighter conjugates of fluorophores multimerized on a polyether scaffold as can be seen in FIG. 2: T helper cells stained with a CD4 conjugate of Alexa Fluor 488 multimerized on a branched PEG (PEG-AF488).” Therefore, it would have been prima facie obvious for the person to have made and used the commercially available Alexa fluor family as taught by Dose to compare the degree of brightness in the conjugate.
The person would have reasonably expected success in using azide and alkyne as the reactive moieties for covalent attachments because Dose recognizes azide and alkyne reactive groups and Kotagiri recognizes using azide and alkyne reactive groups in the presence of maleimide group.
With respect to claim 3, Dose teaches the IgG antibody with 2 to 7 fluorescent polyether labels carrying each 4 to 6 fluorophore groups, resulting in fluorophore DOLs of 8 to 40 dye molecules per antibody molecule (at para. [0059]).
With respect to claim 5, Dose does not teach an average brush distance of 200 to 800 angstrom as claimed. However, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable of degree of labeling an antibody for detection. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation” Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Since applicant has not disclosed that the limitations in claim 5 are for any particular purpose or solve any stated problem, and Dose teaches the results of degree of labeling the antibody with the 8-arm PEG polymer (see Example 1). Absent of unexpected results, it would have been obvious to the person of ordinary skill in the art to discover the distance between fluorescent labels on a multi-arm PEG to produce optimum degree of labeling results.
With respect to claim 6, Dose teaches in Figs. II and III that Z groups are separated with at least 16 covalent bonds, wherein Z is either a fluorophore F group or reactive R group to the antibody (at para. [0036] and Example 1).
With respect to claim 7, Dose teaches in Figs. II and III that Z groups are separated within 16 to 800 covalent bonds, wherein Z is either a fluorophore F group or reactive R group to the antibody (at para. [0036] and Example 1).
With respect to claim 9, Dose teaches the fluorophore F is cyanine dyes (at para. [0037]). Dose also teaches AF488 dye (at Example 1), which would read on a fluorescein dye derivative thereof.
With respect to claim 10, Dose teaches the fluorophore F is cyanine dyes (at para. [0037]). Dose also teaches AF488 dye (at Example 1), which would read on the labels comprising a moiety of xanthene or cyanine.
With respect to claims 12-13, Dose teaches the IgG antibody with 2 to 7 fluorescent polyether labels carrying each 4 to 6 fluorophore groups, resulting in fluorophore DOLs of 8 to 40 dye molecules per antibody molecule (at para. [0059]). Dose teaches in Fig. II of eight Z groups on the PEG conjugate, wherein Z has a plurality of fluorophore F groups or at least one reactive R group to the antibody (at para. [0036]).
Response to Arguments
Applicant’s arguments filed 12/17/2025 have been considered but are moot because Applicant’s amendments necessitated a new ground of rejection. However, the Dose reference will be addressed below as it is used in the current office action.
Applicant argues bottom of page 9 that there is no teaching or suggestion in Dose to utilize the particular molecular weight parameters to reduce the quenching of the fluorescent labels. Dose merely provides a very broad genus of 8-armed polymers and does not provide any data or information motivating the person to utilize 8-armed polymers having molecular weights greater than 10K wherein each arm of the polymer is conjugated to an individual fluorescent label. Applicant further argues on page 10 that Dose’s conjugate is not the same as the claimed invention because the DOL is 5.7 for the recited 8-armed amino-PEG construct. Meanwhile, the claim recites that each arm of the multi-armed polyethylene glycol is conjugated to an individual fluorescent label. Applicant also argues on page 9 that the present application determined that the recited molecular weight limitations for the recited 4 and 8 multi-armed polyethylene glycol polymers where critical in achieving the unexpected superior results exhibited by Applicants’ claimed conjugates, such as the fluorescent ratio values recited by claim 1.
The arguments are not found persuasive for the following reasons. The claims are directed to a conjugate antibody that comprises at least one fluorescently labeled multi-armed polyethylene glycol polymer conjugated to said antibody. (1) As stated in the 112(b) rejection above, the claims are unclear to the boundary of the structure of the multi-armed PEG polymer containing fluorescent labels and (2) Figs. II and III (at para. [0037]) do show the structures of the claimed multi-armed PEG polymers (i.e., greater than 2K MW or 10K MW). Additionally, Figs. II and III also show that p is either n or m wherein n and m are integers from 2 to 500, which would encompass the claimed MWs. Because the claimed range (2K or 10K MW) overlaps with the range disclosed by the prior art in producing the PEG polymer) , a prima facie case of obviousness exists. In other words, it would have been obvious to have produced a multi-armed PEG polymer greater than 2K or 10K MW because Dose recognizes the ability to modify the ethylene glycol units within 2 to 500 per PEG arm. This would also resulted in producing the claimed function.
Additionally, with respect to MW greater than 2K Dalton and comprises four arms, the 8-armed PEG polymer of Dose would also read on the claimed PEG polymer, as the claim recites open-ended recitation (i.e., comprises). In other words, the claims are open to additional PEG arms that do not require fluorescent label attachment. Meanwhile, Dose teaches the IgG antibody with 2 to 7 fluorescent polyether labels carrying each 4 to 6 fluorophore groups, resulting in fluorophore DOLs of 8 to 40 dye molecules per antibody molecule (at para. [0059]).
With respect to superior and unexpected results, the arguments are not found persuasive because Applicant has not provided evidence that commensurate in scope with the claimed subject matter. To show unexpected results, the evidence must be (1) commensurate in scope with the claimed subject matter, In re Clemens, 622 F.2d 1019, 1035, 206 USPQ 289, 296 (CCPA 1980), (2) show what was expected, to "properly evaluate whether a … property was unexpected", and (3) compare to the closest prior art. Pfizer v. Apotex, 480 F.3d 1348, 1370-71, 82 USPQ2d 1321, 1338 (Fed. Cir. 2007).
In this particular case, Example 8 has specific chemical structures of the multi-armed PEG polymers (i.e., either 4 or 8 arms) to produce the superior or unexpected results as disclosed in the specification. Meanwhile, the claims are not commensurate in scope with Example 8 of the specification.
Conclusion
No claim is allowed.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678