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 .
Election/Restrictions
Applicant’s election without traverse of the elected species (see ELC 9/8/2026) in the reply filed on 9/8/2026 is acknowledged. Claims 7 and 10-13 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, and there being no allowable generic or linking claim.
Status of Claims
Withdrawn: 7, 10-13
Examined Herein: 1-6, 8, 9, 14, 15
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in GB 2110867.5 on 7/28/2021 and PCT/EP2022/071262 on 7/28/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/26/2024, 2/23/2024, and 9/8/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
The formulas depicted in the amended claims filed 1/26/2024 are missing characters. The Examiner informed Christopher K. Albert (attorney of record) by phone on 9/23/2026 of this issue and stated that a claim set clearly and accurately depicting all characters in the formulas must be filed. Examination has been conducted based on the corresponding formulas as defined in the specification and as clarified by Applicant’s election of species. However, Applicant must a claim set that clearly and accurately depicts all characters in the formulas.
Claim Rejections - 35 USC § 112
Claims 4 and 5 rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 4 recites the limitation “the CMC derivative comprising at least one unit of Formula 1aa” and “the CMC derivative comprising at least one unit of Formula 1ab.” There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not describe Formula 1aa or 1ab. Dependent claims fall therewith.
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.
Claims 1-6, 9, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Ballamy (US 2019/0307904 A1, Published 10/10/2019), in view of Loka (Conjugation of Synthetic N-Acetyl-Lactosamine to Azide-Containing Proteins Using the Staudinger Ligation, Bioconjugate Chem. 2010, 21, 1842–1849).
With respect to claim 1, Ballamy discloses a method of functionalizing sodium carboxymethylcellulose (Na-CMC)
PNG
media_image1.png
475
1135
media_image1.png
Greyscale
[Ballamy, 0233]
which is a cellulose comprising at least one unit of Formula 0:
PNG
media_image2.png
275
374
media_image2.png
Greyscale
where at least one G0 group is:
PNG
media_image3.png
153
252
media_image3.png
Greyscale
[Ballamy, 0233 (4)]
and the remaining G0 groups are H
the method comprising the steps of:
coupling at least one said unit of Formula 0 with a spacer selected from:
PNG
media_image4.png
110
425
media_image4.png
Greyscale
[Ballamy, 0233 (19)]
where n is 2; to form a CMC derivative comprising at least one unit of Formula 1:
PNG
media_image5.png
454
1001
media_image5.png
Greyscale
[Ballamy, 0233 (12), 0305]
where at least one G1 group is:
PNG
media_image6.png
144
288
media_image6.png
Greyscale
and the remaining G1 groups are H
wherein L is:
PNG
media_image7.png
115
353
media_image7.png
Greyscale
derived from the spacer.
iii) coupling at least one unit of Formula 1 in said CMC derivative with a compound of
Formula: L2-M
wherein:
L2 is a bond,
M is a biomolecular unit, a peptide. [Ballamy, 0233]
With respect to claim 2, Ballamy discloses:
ion exchanging the Na+ in Na-CMC with a R4N+ cation (tetrabutylammonium hydroxide) to form a CMC derivative comprising at least one unit of Formula 1ab, where at least one G1ab group is:
PNG
media_image8.png
159
275
media_image8.png
Greyscale
and the remaining G1ab groups are H. [Ballamy, 0289, 0305, 0306]
(c) reacting at least one said unit of Formula 1ab with the spacer to form the CMC derivative comprising at least one unit of Formula 1. [Ballamy, 0289, 0305, 0306]
With respect to claim 3, Ballamy discloses:
(aa) ion exchanging the Na+ in Na-CMC with a H+ (Dowex 650C monosphere ion exchange resin) to form a CMC derivative comprising at least one unit of Formula 1aa:
where at least one G1aa group is:
PNG
media_image9.png
152
239
media_image9.png
Greyscale
and the remaining G1aa groups are H. [Ballamy, 0233, 0289, 0305, 0306]
(ab) ion exchanging the H+ of at least one said unit of Formula 1aa with a R4+ cation (tetrabutylammonium hydroxide) to form a CMC derivative comprising at least one unit of Formula 1ab. [Ballamy, 0233, 0289, 0305, 0306]
(c) reacting at least one said unit of Formula 1ab with the spacer to form the CMC
derivative comprising at least one unit of Formula 1. [Ballamy, 0233, 0289, 0305, 0306]
With respect to claims 4 and 5, Ballamy discloses that step i) comprises:
(i)(b) activating the -CH2COO-R4N+ group of Formula 1ab by reacting with an activating reagent to form a CMC derivative of Formula 1b:
PNG
media_image10.png
206
344
media_image10.png
Greyscale
wherein at least one G1b group is:
PNG
media_image11.png
166
188
media_image11.png
Greyscale
LG is a leaving group, O-RLG, wherein RLG is:
PNG
media_image12.png
167
152
media_image12.png
Greyscale
(i)(c) reacting Formula 1b with the spacer to form Formula 1. [Ballamy, 0233, 0289, 0305, 0306]
With respect to claim 6, Ballamy discloses that the degree of substitution (DoS) of units
of Formula 1 in the CMC derivative per D-anhydroglucopyranose monomers of cellulose after step i) is at least about 0.25 (= 0.7). [Ballamy, 0306]
With respect to claim 9, Ballamy discloses that the biomolecular unit M is a peptide. [Ballamy, 0233, 0289, 0305, 0306]
Ballamy further discloses that, in some embodiments, the linker L comprises a chemical moiety that is a product of a nucleophilic reaction. In general, the term “nucleophile” is art-recognized to mean a chemical group having a reactive pair of electrons that reacts with a compound by displacing a leaving group (commonly another nucleophile). Illustrative anionic nucleophiles include, inter alia, simple anions such as azide. [Ballamy, 0112]
Ballamy does not disclose that the method comprises step (ii).
However, with respect to claim 1, Loka discloses a method of functionalizing N-Acetyl-Lactosamine (Lac-NAc) comprising the step of:
Coupling at least one unit of Lac-NAc with a reactive member reagent selected from:
PNG
media_image13.png
238
361
media_image13.png
Greyscale
Wherein:
LG1 is a leaving group (-O-maleimide)
L1 is a bond
Rc is alkyl
PNG
media_image14.png
168
217
media_image14.png
Greyscale
[Loka, Figure 1]
To form a Lac-NAc derivative comprising R1
wherein:
R1 is a reactive member derived from the reactive member reagent:
PNG
media_image15.png
217
334
media_image15.png
Greyscale
Wherein:
L1 is a bond
Rc is alkyl
iii) coupling at a Lac-NAc derivative with a compound of Formula B1:
PNG
media_image16.png
114
203
media_image16.png
Greyscale
Wherein:
L2 is –(alkylene)C(O)-
M is a biomolecular unit, B-Lactoglobulin
PNG
media_image17.png
184
213
media_image17.png
Greyscale
[Loka, Figure 1]
wherein the azide functional group of the compound of Formula B1 reacts with R1 of the at least one unit of Lac-NAc derivative via a click reaction to form a Lac-NAc derivative product comprising at least one unit of Lac-NAc derivative comprising at X-R2, wherein:
X is a linker group derived from R1:
PNG
media_image18.png
247
339
media_image18.png
Greyscale
; and
R2 is -L2-M derived from the compound of Formula B1.
PNG
media_image19.png
369
500
media_image19.png
Greyscale
[Loka, Figure 1]
With respect to claim 9, Loka discloses that the biomolecular unit M is a peptide, B-Lactoglobulin. [Loka, Figure 1]
Moreover, Loka discloses that a carbohydrate epitope, a linker, and a phosphane group can react with any azide-containing biomolecule, such as a chemically or metabolically labeled protein, in an aqueous environment. [Page 1844, Col. 2, Paragraph 5]
Modifying the method disclosed by Ballamy by coupling the CMC-amine intermediate with the phosphane reactive member reagent disclosed by Loka, labeling the peptide with azidoactic acid, and coupling the CMC-phosphane reagent intermediate with the azide-labeled peptide results in the method of claims 1 and 15, wherein the method comprises:
Coupling at least one unit of Formula I with a reactive member reagent
PNG
media_image5.png
454
1001
media_image5.png
Greyscale
+
PNG
media_image14.png
168
217
media_image14.png
Greyscale
to form a CMC derivative comprising a unit of Formula 2:
PNG
media_image20.png
491
1270
media_image20.png
Greyscale
[Structure rendered by the Examiner based on the proposed modification of Ballamy. Structure not explicitly depicted in Ballamy or Loka. For illustration purposes only]
iii) coupling at least one unit of Formula 2 in said CMC derivative with a compound of
Formula B1:
PNG
media_image16.png
114
203
media_image16.png
Greyscale
Wherein:
L2 is –(alkylene)C(O)-
M is a biomolecular unit, a peptide;
wherein the azide functional group of Formula B1 reacts with R1 of Formula 2 in said CMC derivative via a click reaction to form a CMC derivative of Formula 3:
PNG
media_image21.png
454
1184
media_image21.png
Greyscale
[Structure rendered by the Examiner based on the proposed modification of Ballamy. Structure not explicitly depicted in Ballamy or Loka. For illustration purposes only]
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Ballamy by coupling the CMC-amine intermediate with the phosphane reactive member reagent disclosed by Loka, labeling the peptide with azidoactic acid, and coupling the CMC-phosphane reagent intermediate with the azide-labeled peptide, and have a reasonable expectation of success. Ballamy discloses a method for preparing a functionalized CMC conjugating a CMC derivative comprising a free-terminal amine to a peptide via a covalent linkage. Ballamy further discloses that the CMC derivative may be conjugated to the peptide via a linker comprising a chemical moiety that is a product of a nucleophilic reaction, including with an azide nucleophile. Loka discloses a LacNAc derivative conjugated to a modified peptide via a phosphane reagent. Specifically, the LacNAc derivative, which bears a terminal amine, is acylated with a phosphane reagent, and the peptide is labeled with an azidoacetic acid. The LacNAc-phosphane reagent conjugate reacts with the azide-modified protein via Staudinger ligation to form a stable conjugate. Ballamy establishes that azide is a known nucleophile used for forming covalent linkages via a nucleophilic reaction and that CMC is a polymeric carbohydrate. Loka demonstrates a carbohydrate may be functionalized with a protein by reacting a carbohydrate-phosphane intermediate with an azide-modified protein via a Staudinger ligation reaction. Accordingly, the combined teachings of Ballamy and Loka reasonably suggest that the CMC derivative disclosed by Ballamy may be functionalized with an azide-modified protein via a Staudinger ligation reaction by acylating the terminal amine with a phosphane reagent, labeling the peptide with azidoacetic acid, and reacting the intermediates to form a stable conjugate. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Loka discloses that chemoselective ligation of glycans allows for combining a biologically isolated protein with a synthetic glycan. [Loka, Page 1842, Col. 1, Paragraph 2] Modifications to the cell-surface of glycans have been used to alter biological responses, inducing immune targeting and modifying cellular adhesion. [Loka, Page 1842, Col. 2, Paragraph 1] Moreover, the chemoselective strategy, Staudinger ligation, provides an efficient route to forming glyconjugates under extremely mild conditions that are compatible with proteins and live cells. [Loka, Page 1848, Col. 1, Paragraph 2] Moreover, the method could be used to increase the biological half-life of therapeutic proteins through attachment of defined glycans. [Loka, Page 1848, Col. 1, Paragraph 1] Therefore, one would have been motivated by the expectation that coupling the CMC-amine intermediate with the phosphane reactive member reagent disclosed by Loka, labeling the peptide with azidoacetic acid and coupling the CMC-phosphane reagent intermediate with the azide-labeled peptide would yield a glycoconjugate that is compatible with proteins and live cells and that can increase the biological half-life of therapeutic proteins through attachment of defined glycans.
Claims 1-6, 8, 9, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Ballamy and Loka is applied to claims 1-6, 8, 9, and 15 above, and further in view of Do (US 2014/0302001 A1, Published 10/9/2014).
With respect to claim 1, Ballamy and Loka disclose the teachings above.
With respect to claim 8, Ballamy and Loka disclose that the reactive member reagent is:
PNG
media_image14.png
168
217
media_image14.png
Greyscale
[Loka, Figure 1]
And represented by the following formula:
PNG
media_image22.png
239
348
media_image22.png
Greyscale
Wherein, R1 is:
PNG
media_image23.png
203
282
media_image23.png
Greyscale
X is:
PNG
media_image24.png
194
282
media_image24.png
Greyscale
LG1 is:
PNG
media_image25.png
172
162
media_image25.png
Greyscale
Ballamy and Loka do not disclose that LG1 is:
PNG
media_image26.png
225
264
media_image26.png
Greyscale
However, with respect to claim 8, Do discloses a Staudinger ligation reaction in which a lysosomal enzyme is mofidied with phosphine and conjugated to an azide-modified targeting peptide using either NHS-phosphine or sulfo-NHS-phosphine as suitable crosslinking agents. [Do, 0025, Figure 2]
Modifying the method disclosed by Ballamy and Loka by replacing the reactive member agent, NHS-phosphine, with sulfo-NHS-phosphine results in the method of claim 8, wherein:
LG1 is:
PNG
media_image26.png
225
264
media_image26.png
Greyscale
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Ballamy and Loka by replacing the reactive member agent, NHS-phosphine, with sulfo-NHS-phosphine and have a reasonable expectation of success. Ballamy and Loka disclose a method comprising a Staudinger ligation reaction, wherein a reactive member agent, NHS-phosphine, crosslinks a Na-CMC group to a peptide. Do discloses a method comprising a Staudinger ligation reaction, wherein a reactive member agent, NHS-phosphine or sulfo-NHS-phosphine, crosslinks an enzyme to an azide-modified peptide.
Accordingly, the combined teachings of Ballamy/Loka and Do suggest that sulfo-NHS-phosphine may funceiton as the reactive member reagent in the Staudinger ligation reaction of the method disclosed by Ballamy and Loka because Do establishes that, in such a reaction, either NHS-phosphine or sulfo-NHS-phosphine is a suitable crosslinking agent. One would have been motivated to do so because substituting equivalents known for the same purpose when their equivalency is recognized in the prior art is prima facie obvious. MPEP 2144.06(II). In the present case, Do discloses that in a Staudinger ligation reaction either NHS-phosphine or sulfo-NHS-phosphine is a suitable crosslinking agent. [Do, 0025, Figure 2] Therefore, modifying the method disclosed by Ballamy and Loka by replacing one crosslinking agent (NHS-phosphine) with another (sulfo-NHS-phosphine) is prima facie obvious.
Allowable Subject Matter
Claim 14 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
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILA A CRAIG whose telephone number is (703)756-4540. The examiner can normally be reached Monday-Friday 0800-1600.
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.
/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights