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 .
Summary
Claims 15-18 and 20-35 are pending in this office action. Claims 20-35 are new. Claims 1-14 and 19 are cancelled. All pending claims are under examination in this application.
Priority
The current application filed on March 21, 2023 is a 371 of PCT/EP2021/076180 filed September 23, 2021. The current application claims foreign priority to EP21167124.3 filed on April 7, 2021, and EP20197699.0 filed September 23, 2020.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on June 6, 2025 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claims 15-18 and 20-33 are objected to because of the following informalities:
Claim 15 has the text “…comprising a compound, the compound comprising…” This text should be deleted and “the composition comprising” should be inserted within the body of the claim. Furthermore, there should be a hyphen between “…anti-polyethylene glycol…”
Dependent claims 16-18 and 20-33 fail to cure the defects of claim 1.
Claim 33 needs a period at the end of the claim.
Claims 34 and 35 use “(i-a).” Please delete this designation, and use “-“, similar to claim 1. Since there is no (i-b), a – is more appropriate.
Claim 35 uses “(iii-a).” Please delete this designation and use “-“, similar to claim 1. Since there is no (iii-b), a – is more appropriate.
Appropriate correction is required.
Claims 15-18 and 20-35 are rejected under 35 U.S.C. 103 as being unpatentable Lai et al. (WO2019/046185A1, published in March 2019) in view of Dintzis et al. (US6,022,544A), Bellocq et al. (Bioconjugate Chemistry, 2003), Kim et al. (Journal of Controlled Release, 2012), Martinez et al. (US2004/0062748A1) and Regev et al. (WO2017/075465A1).
[The Examiner is going to introduce each reference and then combine them in the rejection of the instant claims.]
1. Lai et al.
Lai et al. is considered to be the closest prior art as it teaches use of high molecular weight polyethylene glycol compositions to restore the efficacy of PEGylated therapeutic compositions (see title). Furthermore, Lai et al. disclose that the present disclosure relates to methods of reducing accelerated blood clearance of at least one pegylated therapeutic composition in a subject suffering from a disease and in need of treatment. The methods involve administering at least one high molecular weight polyethylene glycol composition to a subject suffering from a disease. The administration of at least one high molecular weight polyethylene glycol composition can also be used to increase the circulation half-life of at least one PEGylated therapeutic composition as well as restore the pharmacokinetics of the PEGylated therapeutic composition in a subject having a high titer of anti-polyethylene glycol antibodies (see abstract).
2. Dintzis et al.
Dintzis et al. teach therapeutic suppression of specific immune responses by
administration of oligomeric forms of antigen of controlled chemistry (see title). In addition, Dintzis et al. disclose that the invention features a method for reducing an undesired antibody response in a mammal by administering to the mammal a non-immunogenic construct which is free of high molecular weight immunostimulatory molecules. The construct which contains at least two copies of a B cell membrane
immunoglobulin receptor epitope bound to a pharmaceutically acceptable non-immunogenic carrier directly binds to B cell membrane immunoglobulin receptors but
fails to form an immunon (see abstract).
3. Bellocq et al.
Bellocq et al. teach transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery (see title). Also, Bellocq et al. disclose that transferrin is a well-studied ligand for tumor targeting due to upregulation of transferrin receptors
m numerous cancer cell types. Here, we report the development of a transferrin-modified, cyclodextrin polymer-based gene delivery system. The delivery system is comprised of a nanoparticle (formed by condensation of a cyclodextrin polycation with nucleic acid) that is surface-modified to display poly(ethylene glycol) (PEG) for increasing stability in biological fluids and transferrin for targeting of cancer cells that express transferrin receptor. A transferrin-PEG-adamantane conjugate is synthesized for nanoparticle modification. The transferrin conjugate retains high receptor binding and self-assembles with the nanoparticles by adamantane (host) and particle surface cyclodextrin (guest) inclusion complex formation. At low transferrin modification, the particles remain stable in physiologic salt concentrations and transfect K562 leukemia cells with increased efficiency over untargeted particles. The increase in transfection is eliminated when transfections are conducted in the presence of excess free transferrin. The transferrin-modified nanoparticles are appropriate for use in the systemic delivery of nucleic acid therapeutics for metastatic cancer applications (see abstract).
4. Kim et al.
Kim et al. teach PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting (see title). Furthermore, Kim et al. disclose that Transferrin (Tf) is considered an effective tumor-targeting agent, and PEGylation effectively prolongs in vivo pharmacokinetics by delaying excretion via the renal route. The authors describe the active tumor targeting of long-acting Tf–PEG–TNF-related apoptosis-inducing ligand conjugate (Tf–PEG–TRAIL) for effective cancer therapy. Tf–PEG–TRAIL was prepared using a two-step N-terminal specific PEGylation procedure using different PEGs (Mw: 3.4, 5, 10 kDa). Eventually, only 10 kDa PEG was linked to Tf and TRAIL because TRAIL (66 kDa) and Tf (81 kDa) were too large to link to 3.4 and 5 k Da PEG. The final conjugate Tf–PEG10K–TRAILwas successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf–PEG10K–TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf–PEG10K–TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG10K–TRAIL demonstrated no specificity. Biodistribution patterns and antitumor effects were investigated in C57BL6 mice bearing B16F10 murine melanomas and BALB/c athymic mice bearing HCT116. Tumor accumulation of Tf–PEG10K–TRAIL was 5.2 fold higher (at 2 h) than TRAIL, because Tf–PEG10K–TRAIL has both passive and active tumor targeting ability. Furthermore, the suppression of tumors by Tf–PEG10K–TRAIL was 3.6 and 1.5 fold those of TRAIL and PEG10K–TRAIL, respectively. These results suggest that Tf–PEG10K–TRAIL is a superior pharmacokinetic conjugate that potently targets tumors and that it should be viewed as a potential cancer therapy (see abstract).
5. Martinez et al.
Martinez et al. teach polymer conjugates with decreased antigenicity, methods of preparation and uses thereof (see title). In addition, Martinez et al. disclose that methods are provided for the preparation of conjugates of a variety of bioactive components, especially proteins, with water-soluble polymers [e.g., poly(ethylene glycol) and derivatives thereof], which conjugates have reduced antigenicity and immunogenicity compared to similar conjugates prepared using poly(ethylene glycol) containing a methoxyl or another alkoxyl group. The invention also provides conjugates prepared by such methods, compositions comprising such conjugates, kits containing such conjugates or compositions and methods of use of the conjugates and compositions in diagnostic and therapeutic protocols (see abstract).
6. Regev et al.
Regev et al. teach compositions and methods for evaluating and modulating immune responses by detecting and targeting GATA3 (see title). Furthermore, Regev et al. disclose that the present invention provides markers, marker signatures and
molecular targets that correlate with dysfunction of immune cells and are advantageously independent of the immune cell activation status. The present
markers, marker signatures and molecular targets provide for new ways to evaluate and modulate immune responses. Specifically, GATA3 and/or FOX-01 modulation are provided for use as markers, marker signatures and molecular targets. Therapeutic methods are also provided to treat a patient in need thereof who would benefit from an increased immune response (see abstract).
Combination of Lai et al., Dintzis et al., Bellocq et al., and Kim et al.
Regarding instant claim 15, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach a method of selective depletion of at least one undesirable anti polyethylene glycol (PEG) antibody. The necessary citations within Lai et al., Dintzis et al., Bellocq et al., and Kim et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 15
Lai et al., Dintzis et al., Bellocq et al., and Kim et al. Citations
A method of selective depletion of at least one undesirable anti polyethylene glycol (PEG) antibody the method comprising the following steps:
Lai et al. disclose a method of reducing the formation of anti-PEG antibodies in a subject and in need of treatment or continued treatment thereof (see claim 36 within Lai et al.).
(i) identifying an individual in need of treatment with a PEG-comprising active agent, wherein the individual has the at least one anti-PEG antibody;
Lai et al. disclose the identification of anti-PEG antibodies (APA) from blood (see page 55, paragraph 2 within Lai et al.). In this manner, APAs are identified within a subject.
(ii) -obtaining a pharmaceutical composition comprising a compound, the compound comprising
- a biopolymer scaffold, wherein the biopolymer scaffold is a transferrin, and
- at least two PEG chains bound to the biopolymer scaffold
Lai et al. disclose the use of high molecular weight free PEG can be used to increase the circulation half-life of at least one pegylated therapeutic composition as well as restore the pharmacokinetics of the pegylated therapeutic composition in a subject having a high titer of anti-polyethylene glycol antibodies (see abstract within Lai et al.).
Lia et al. does not disclose the use of a biopolymer scaffold. However, both Bellocq et al. and Kim et al. do disclose transferrin biopolymers (see title and abstract within both Bellocq et al. and Kim et al.). Furthermore, specifically Bellocq et al. disclose the formation of 2 and 3 PEG (5000 g/mol) groups covalently bonded to transferrin (see Figure 3A and page 1127, paragraph 2 within Bellocq et al.).
Dintzis et al. further supports the use of conjugates and peptides to covalently bond scaffolds (see Examples 5A and 5B within Dentzis et al.).
(iii) administering an effective amount of the pharmaceutical composition to the individual to selectively deplete the at least one anti-PEG antibody; and
In a similar fashion to the administration protocol within Lai et al. the high molecular weight PEG is used as a method of reducing the formation of anti-PEG antibodies (see abstract, claims 1 and 36, and pages 2-12 within Lai et al.). [The instant application uses the covalently bound PEG groups on the biopolymer scaffold.]
(iv) administering an effective amount of the active agent to the individual.
In addition to the similar protocol disclosed above, a PEG-active agent is administered after step iii (see page 11 and 12 bridging paragraph and page 12 paragraph 2 within Lai et al.). Additionally, a skilled artisan could expand the active agents to include non-PEG therapeutic agents under routine experimental conditions via administration.
Therefore, a skilled artisan (POSITA; person having ordinary skill in the art) would combine the disclosures of Lai et al., Dintzis et al., Bellocq et al., and Kim et al. to teach all the elements of instant claim 1.
[The remainder of the instant claims are either directly or indirectly dependent on instant claim 1, which is taught in full by the combination of Lai et al., Dintzis et al., Bellocq et al., and Kim et al.]
Regarding instant claim 16, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein the active agent is PEGylated. Please see the discussion and citations within instant claim 1 for the necessary rejection text [step (iv)].
Regarding instant claims 20-24, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach modifying the administration protocol in the appropriate manner. A skilled artisan (POSITA) would modify the administration protocol to obtain the desired claim limitations. The Lai et al. disclosure, for example, would be a suitable template for a POSITA to follow.
Regarding instant claim 25, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein a second titer of the at least one anti-PEG antibody is determined in the individual after performing step (iii) and before performing step (iv), wherein the second titer is lower than the first titer. Lai et al. disclose a method of reducing or attenuating the formation of anti-PEG antibodies or a high-titer of anti-PEG antibodies in a subject
that is suffering from a disease and in need of treatment or repeated treatment thereof. The method comprises the step of administering from about 1 to about 2500 milligrams per kilogram of at least one high molecular weight polyethylene glycol composition, from about 1 to about 2500 milligrams per kilogram of at least one low molecular weight polyethylene glycol composition or from about 1 to about 2500 milligrams per kilogram of a combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition to a subject either prior to administration of at least one pegylated therapeutic composition (e. g., namely, before the start of treatment of any kind) or that has previously been administered at least one pegylated therapeutic composition (and will receive subsequent treatments with the at least one pegylated therapeutic or an alternative pegylated therapeutic) (see pages 10-11, bridging paragraph within Lai et al.). In this manner, a reduction in the titer would be observed titer of the at least one anti-PEG antibody prior to administration of the active agent. A skilled artisan (POSITA) could meet this instant claim 25 limitation under routine conditions.
Regarding instant claim 26, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein the administration in step (iii) is intravenous administration. Lai et al. disclose an intravenous administration of the protocol of their invention/method (see Example 1 within Lai et al.).
Regarding instant claim 27, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein the transferrin is human transferrin. Bellocq et al. disclose the use of human transferrin (see page 1124, left column, 3rd paragraph within Bellocq et al.).
Regarding instant claim 28, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein the individual is a human. Lia et al. disclose wherein the individual is human (see page 21, 4th paragraph within Lai et al.).
Regarding instant claim 29, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein at least a portion of the one or more PEG chains are covalently bound to the biopolymer scaffold via at least one linker. Bellocq et al. disclose wherein at least a portion of the one or more PEG chains are covalently bound to the biopolymer scaffold via at least one linker (see Figures 1 and 2 within Bellocq et al.).
Regarding instant claim 31, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein at least one of the at least two PEG chains has a molecular weight of 100-10000 Da. Bellocq et al. disclose wherein at least one of the at least two PEG chains has a molecular weight of 100-10000 Da (see Figure 2 within Bellocq et al.; PEG 5000 g/mol).
Regarding instant claim 33, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach wherein the molar ratio of PEG chains to biopolymer scaffold in the composition is from 2:1 to 100:1. Bellocq et al. disclose wherein the molar ratio of PEG chains to biopolymer scaffold in the composition is from 2:1 to 100:1 (see page 1124, right column, 1st paragraph within Bellocq et al.; 2:1).
Regarding instant claims 34 and 35, Lai et al., Dintzis et al., Bellocq et al., and Kim et al. teach the modification of instant method claim 15. Please see the discussion and citations within instant claims 1 and 20 through 24 for the necessary rejection text. A skilled artisan (POSITA) with the above references would be able to successfully modify the instant method to incorporate the new instant limitations.
Combination of Lai et al., Dintzis et al., Bellocq et al., Kim et al., and Martinez et al.
Regarding instant claim 17, Lai et al., Dintzis et al., Bellocq et al., Kim et al., and Martinez et al. teach wherein the active agent is a viral vector or a protein or peptide, selected from the group of enzymes, enzyme inhibitors, antibodies, antibody fragments, antibody mimetics, antibody-drug conjugates, hormones, growth factors, clotting factors and cytokines. Martinez et al. disclose active agents that are peptides and proteins (see claim 26 within Martinez et al.). Martinez et al. further disclose these can be blood clotting factors, a cytokine, hormones, growth factors, enzymes, or antibodies (see claims 27-32; also see Examples 1-2 and 4; both within Martinez et al.).
Regarding instant claim 30, Lai et al., Dintzis et al., Bellocq et al., Kim et al., and Martinez et al. teach wherein the at least one linker comprises a peptide. Both Martinez et al. (see Example 5 within Martinez et al.) and Dintzis et al. (see column 31, lines 5-19 within Dintzis et al.) disclose the use of linker groups in general terms. Furthermore, Bellocq et al. uses an amino acid, a carbohydrate, and a sulfone group with transferrin as linkers (see Figures 1 and 2 within Bellocq et al.). A skilled artisan (POSITA) would be able to expand the linker groups to include a peptide under routine conditions (peptide linkers are common within the art).
Regarding instant claim 32, Lai et al., Dintzis et al., Bellocq et al., Kim et al., and Martinez et al. teach wherein at least one of the at least two PEG chains has a free methoxy end group. Martinez et al. disclose a covalently linked to mPEG (methoxy terminated-PEG) having the molecular weight of 200 Da, 1900 Da, and 5000 Da to a rabbit anti-human erythrocyte IgG (see paragraph [0022]; also see claim 7; both within Martinez et al.). A skilled artisan (POSITA) could employ the use of mPEG within the transferrin biopolymer scaffold of Bellocq et al.
Combination of Lai et al., Dintzis et al., Bellocq et al., Kim et al., and Regev et al.
Regarding instant claim 18, Lai et al., Dintzis et al., Bellocq et al., Kim et al., and Regev et al. teach wherein the active agent is a nucleic acid-lipid particle, a nucleic acid-polymer particle, a nucleic acid-lipid-polymer particle, or a nucleic acid; wherein the nucleic acid is RNA, mRNA or siRNA, or DNA. Regev et al. disclose the use of nucleic acid, siRNA (see paragraph [00340] within Regev et al.). Furthermore, Regev et al. disclose assembly of a nanoplex that is PEGylated (see paragraph [00401] within Regev et al.). Therefore, a skilled artisan would be able to incorporate a siRNA active agent into the biopolymer scaffold containing two PEG chains.
Analogous Art
The Lai et al., Dintzis et al., Bellocq et al., Kim et al., Martinez et al., and Regev et al. references are all applicable to the endeavor of the instant application. Therefore, these teachings make the references relevant to instant claims 15-18 and 20-35.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of reducing accelerated blood clearance of at least one pegylated therapeutic composition by anti-PEG antibodies disclosed by Lai et al. using the teachings of Dintzis et al., Bellocq et al., Kim et al., Martinez et al., and Regev et al. to incorporate the necessary claim limitations. Starting with Lai et al., the skilled person only had to try the necessary claim limitations disclosed by Dintzis et al., Bellocq et al., Kim et al., Martinez et al., and Regev et al. The combination of Lia et al., Dintzis et al., Bellocq et al., Kim et al., Martinez et al., and Regev et al. would allow one to arrive at the present application without employing inventive skill. This combination of the method of reducing accelerated blood clearance of at least one pegylated therapeutic composition by anti-PEG antibodies taught by Lia et al. along with the use of the necessary claim limitations taught by Dintzis et al., Bellocq et al., Kim et al., Martinez et al., and Regev et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the method of reducing accelerated blood clearance of at least one pegylated therapeutic composition by anti-PEG antibodies disclosed by Lia et al. with the use of the necessary claim limitations taught by Dintzis et al., Bellocq et al., Kim et al., Martinez et al., and Regev et al. This combined modification would have led to an enhanced method of selective depletion of at least one undesirable anti-polyethylene glycol (PEG) antibody that would be beneficial for patients.
Response to Arguments
Applicant's arguments filed December 1, 2025 have been fully considered but they are not persuasive.
The instant claim amendments were sufficient to address the claim objections, 35 U.S.C. 112(b) rejections, and 35 U.S.C. 101 rejections. Therefore, they are all withdrawn from the Non-Final office action dated May 30, 2025.
The amendments and new instant claims did necessitate new grounds of rejection including the addition of the Dintzis et al., Bellocq et al., and Kim et al. citations.
Applicant Argument: The Applicant argues that amended instant claim 15 is not taught by the references of record.
Examiner’s Rebuttal: The argument is now moot. The amendments and new instant claims prompted the Examiner to necessitate new grounds of rejection. Therefore, the references of record have changed accordingly as shown above. A new 35 U.S.C. §103 rejection is presented within the office action.
Applicant Argument: The Applicant argues that the unexpected results support allowability of the present application.
Examiner’s Rebuttal: The references for the support of the prima facie obviousness rejection are not able to be removed by the strength of the unexpected results. [Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (Claims directed to a method of effecting analgesia without producing physical dependence by administering the levo isomer of a compound having a certain chemical structure were rejected as obvious over the prior art. Evidence that the compound was unexpectedly nonaddictive was sufficient to overcome the obviousness rejection. Although the compound also had the expected result of potent analgesia, there was evidence of record showing that the goal of research in this area was to produce an analgesic compound which was nonaddictive, enhancing the evidentiary value of the showing of nonaddictiveness as an indicium of nonobviousness.). See MPEP § 716.01(d) for guidance on weighing evidence submitted to traverse a rejection.]
Examiner’s Comment: It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Thus, the 35 U.S.C. §103 rejection for instant claims 15-18 and 20-35 is maintained.
Conclusion
No claims are allowed.
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.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615