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 .
Status of Claims
Claims 2, 4, 11, and 12 are cancelled. Claims 25-28 are new. Claims 1, 3, 5-10 and 13-28 are pending. Claims 19-24 are withdrawn. Claims 1, 3, 5-10, 13-18 and 25-28 are under examination.
Priority
This application claims priority to US provisional application 63/321,125 filed on 3/18/2022.
Rejections Withdrawn
The rejection under USC 101 is withdrawn per applicant’s amendments and arguments.
The rejection under USC 112(b) for the manner “optionally” is used in the claim is withdrawn per applicant’s removal of the “optionally”.
The rejections under USC 112(d) over the claims is withdrawn per applicant’s amendments and arguments.
The rejections under USC 102 over Pourcelle and over van Lith are withdrawn per applicant’s amendments and arguments.
The rejection under USC 103 over Pourcelle is withdrawn per applicant’s amendments and arguments.
The rejection under USC 103 over Pourcelle and Lee is withdrawn as the van Lith reference is also incorporated after applicant’s amendments to the claims.
As these rejections are withdrawn, applicant’s arguments to these rejections are now moot. The examiner will respond to arguments on maintained rejections.
New Claim Objection- As Necessitated by Amendment
Claim Objection
Claim 27 is objected to for “between 5:1,” since the claim should read “ratio of 5:1, or 3:1, or 1:1.”
Appropriate correction is required.
Maintained Rejections – Modified As Necessitated by Amendments
Claim Rejections - 35 USC § 112(b)
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 1, 3, 5-10, 13-18 and 25-28 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.
Maintained 112(b) Rejections – Modified As Necessitated by Amendments/Cancellations
Claim 1 is indefinite for utilizing “comprising” for the composition followed by “consisting of” for “an interactive two component system” followed by another “comprising” when “optionally” defining the crosslinking component that is within the two component system that was closed for “the two components” with “consisting of”. This change in transition phrases from “comprising” to “consisting of” to additional “comprises/comprising” within the two components makes it unclear how and what the composition is open and closed to. Furthermore, now each of the first component and second component use “comprises” with additional components having “comprises” within the two components provided with “consisting of”. For the purpose of compact prosecution, if the prior art teaches a composition with component limitations as claimed, then it will read on the claim. Applicant should consider amending recitations of “comprising/comprises” or similar such transition phrases to “is”, “consist”, or other like language when it comes to any components of claim 1 and its dependent claims that are found within “the two components consisting of”.
Claims 3, 5-10, 13-18 and 25-28 are withdrawn as being dependent on an indefinite claim without repairing the issue of indefiniteness.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 15 recites the broad recitation “small molecule crosslinker or polymeric crosslinker”, and the claim also recites “optionally wherein the small molecule crosslinker or polymeric crosslinker is bivalent or multivalent”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note that in this case, “optionally” is not necessarily being used as an “or” and is not used in the form A, B and optionally C, where the C ingredient is not needed, but rather to introduce narrower instances of crosslinking component, where it is unclear if applicant wants these narrower forms to be required for consideration of the claim limitation. Applicant may either delete “optionally” or delete the entire recitation starting from “, optionally” and make a new dependent claim that indicates “…wherein the small molecule crosslinker or polymeric crosslinker is bivalent or multivalent.” For the purpose of compact prosecution, the small molecule crosslinker or polymeric crosslinker” in claim 1 will be considered if it is any form/type in the prior art.
Claims 16-17 are rejected as being dependent on indefinite claims.
New 112(b) Rejections – As Necessitated by Amendment (Claim 1 was amended to include a first component comprises and a second component comprises while providing limitations toward first component and second component)
Claim 1 is indefinite for “the first component comprises reactive moieties to react….” as initially the first component is indicated as “first component comprises a targeting agent conjugated…”. It is unclear if the reactive moieties are part of the same compound/polymer with the targeting agent or if the reactive moieties may be present in other components present in the first component.
Claim 1 is indefinite for “the second component comprises a corresponding moiety to react with the first component….” as initially the first component is indicated as “second component comprises a crosslinking agent…”. It is unclear if the corresponding moieties are part of the same compound/polymer with the targeting agent or if the reactive moieties may be present in other components present in the second component.
Claims 3, 5-10, 13-18 and 25-28 are withdrawn as being dependent on an indefinite claim without repairing the issue of indefiniteness.
Claim 5 is indefinite for “the polypeptide sequence binds to…….a von Willebrand factor” as claim 1 now indicates the polypeptide sequence comprises a ligand for a receptor, however, “von Willebrand factor” is a factor and not a receptor, and thus, would not be able to bind the polypeptide sequence with ligand.
Claim 7 is indefinite for “first component comprises a hydrophilic component and a hydrophobic component, wherein the polypeptide sequence is covalently attached to the hydrophilic component” as it becomes unclear if the hydrophobic component is part of the same polymer/compound with the polypeptide sequence and hydrophilic component or if the hydrophobic component may remain as a separate agent.
Claim 7 is indefinite for the recitation of “the first component comprises a hydrophilic component and a hydrophobic component” as claim 1 provides the first component as “comprises a targeting agent…”. It is unclear if the first component is being redefined in claim 7 or if these are further components for the first component with what it was made up of in claim 1.
Claims 8-10 are rejected as being dependent on an indefinite claim.
Claims 15 and 28 are indefinite for the recitation of “comprises nanoparticles” or “mg/ml of nanoparticles” without referring to which nanoparticles found in claim 1 they are referring to. Note there is “a synthetic nanoparticle” found as an option in the first component and “a synthetic nanoparticle” found as an option under the second component. It is unclear if applicant is referring to these synthetic nanoparticles or if there may be additional nanoparticles to these synthetic nanoparticles (for example, natural nanoparticles) and applicant is considering a total of all nanoparticles.
Claims 16, 17 and 26-27 are rejected as being dependent on an indefinite claim.
Claim 28 recites the limitation "the nanoparticles" in line 3 but previous recitations are “synthetic nanoparticles” in claim 1 or “azide functionalized nanoparticles” earlier in claim 28. There is insufficient antecedent basis for this limitation in the claim. It also becomes unclear whether the azide functionalized nanoparticles are different or the same as the nanoparticles comprising a GRGDS polypeptide, PEG and PLGA.
New Rejection – As Necessitated by Amendments
Claim Rejections - 35 USC § 112(d)
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.
Claim 15 is 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. Claim 15 provides that “the second component comprises a small molecule crosslinker or polymeric crosslinker, optionally wherein the small molecule crosslinker or polymeric crosslinker is bivalent or multivalent” while claim 1 notes the option as being “a synthetic bivalent or multivalent small molecule or a bivalent or multivalent synthetic polymer” where the bivalent or multivalent is not optional. Thus, through this limitation, claim 15 does not further limit what is presented in claim 1. 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, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Maintained Rejection – Modified As Necessitated by Amendment
Claims 1, 3, 5-10, 13-17 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Pourcelle et al (Biomacromolecules, Nov 2007, volume 8, pages 3977-3983) and van Lith et al (Bioconjugate Chemistry, 2017, volume 28, pages 539-548).
The claim is toward a composition/product. Recitation of “hemostatic” and “at site of injury” are toward the intended use of the formulation. If the prior art teaches the components (i.e. targeting agent with polypeptide and crosslinking agent as claimed), then it reads on the claim. The presence of the crosslinking agent along with targeting agents that can be crosslinked will allow for the crosslinking at any site.
Pourcelle teaches PCL-PEG based nanoparticles grafted with GRGDS peptide (Tables 1 and 3 and title, PCL-PEG-g-GRGDS). Pourcelle provides for an 4-(p-Azidophenyl)-N-succinimidyl butanoate (bioorthogonal group/reagent) that attaches to the copolymer (Scheme 1). Pourcelle teaches solubilizing PCL-PEGs with molecular clip in creating the version of the PCL-PEG that has the functional group that links to GRGDS when immersed with the GRGDS (page 3977, polymer chemistry and Conclusion). Therefore, GRGDS remains separate from the linkable/activated PCL-PEG until they are immersed together. Pourcelle teaches the preparation of the nanoparticles on page 3981. Pourcelle also provides for PLGA and PLGA-PEG for the nanoparticles (page 3981). PCL is hydrophobic and PEG is hydrophilic. Pourcelle teaches hydrolytically degradable polyesters (first column page 3980). Pourcelle teaches average nanoparticle sizes of 192 nm for the PCL-PEG-g-GRGDS-2 (table 2). The conclusion of Pourcelle indicates that it is confirmed that the targeting is due to the RGD sequence and not just the nature of the particles. Pourcelle teaches “Nanoscopic particles self-assembled from amphiphilic block copolymers have been developed over the past years for the preparation of various drug delivery systems. The biodegradable carriers made of polyethylene glycol (PEG)-polyester diblock copolymers emerged as the most adequate devices due to their prolonged circulation half-life in blood, their ability to bypass natural barriers, their reduced rate of uptake by liver, and their controllable delivery potentiality” (page 3977). Pourcelle teaches the preparation of the nanoparticles on page 3981. Pourcelle also provides for PLGA and PLGA-PEG for the nanoparticles (page 3981). PCL is hydrophobic and PEG is hydrophilic. Pourcelle teaches hydrolytically degradable polyesters (first column page 3980).
Pourcelle does not teach using the linking system with agents like DBCO or azide.
van Lith teaches attaching PEG on molecules to either azide or DBCO so that alkyne-azide cycloaddition can be used to connect molecules (abstract, also figure 3). This would allow the crosslinker component on the PEG portion of a molecule. van Lith provides for an approach to prepare molecularly defined targeted nanoparticles with preserving targeting potential and removing unwanted tags (conclusion). van Lith teaches PEGylation of an antibody and then addition of an azide group while also addition of DBCO onto a nanoparticle (abstract). This offers a click chemistry where the antibody can be crosslinked to the nanoparticle. Thus, both the azide-PEG-antibody and the DBCO-nanoparticle can act as crosslinking components and the antibody portion can act as a targeting component. The abstract notes that the DBCO or azide can be used on either part. This strategy is also noted in figure 6. van Lith notes that PEGylation is also important on nanoparticles and notes PCL-mPEG diblock micelles (first column of 544). Here, resulting micelle particles are 28 nm (page 544). van Lith teaches the bioorthogonal site-specific conjugation (conclusion). van Lith notes the potential for making targeted nanoparticles (conclusion). Since van Lith teaches the components separate until the linking occurs, it recognizes the two component system. van Lith teaches making antibodies with the click moieties and also making Ben-PCL7-PEG2000-DBCO to also make them clickable (pages 545-546).
One of ordinary skill in the art before the time of filing would have seen the availability of bioorthogonal click-crosslinkers, polymers and nanoparticles, and targeting moieties with polypeptides as taught by Pourcelle and van Lith and would have sought to provide new systems for targeted molecules that have the ability to be crosslinked as part of a two component system. One of ordinary skill in the art before the time of filing would have seen use of azides and/or DBCO of van Lith as suitable approaches to link/click molecules together and that these groups can be attached to PEG groups in a molecule for linking to other molecules as in teachings of Pourcelle. As van Lith notes its approach aids to prepared targeted nanoparticles with preserving targeting potential, a person of ordinary skill in the art with the teachings of Pourcelle would be motivated to use such a strategy to link the GRGDS for targeting to copolymer nanoparticles with a reasonable expectation of better preserving targeting ability. In regard to stochiometric ratio, this would be adjusted depending on the number of targeting components to be crosslinked/clicked to a nanoparticle. Thus, one of ordinary skill in the art would desired at least 1 mole of first component to react with one mole of second component.
New Rejections – As Necessitated by Amendments and New Claims
Claim 18, 26 and 28 in addition to claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Pourcelle et al (Biomacromolecules, Nov 2007, volume 8, pages 3977-3983), van Lith, and Lee WO 2021125805A1.
Pourcelle and van Lith teach the claims as discussed above.
Pourcelle and van Lith do not teach the packaged product of claim 18 where items are kept separate until use.
Lee teaches “a first chamber containing an amphiphilic block copolymer, a cationic compound, and a polylactate; and A second chamber containing an active ingredient selected from a nucleic acid, a polypeptide, a virus, or a combination thereof; A kit for preparing a nanoparticle composition” (claims and abstract). Lee provides for preparation of the nanoparticles by mixing of the components (abstract). As Lee teaches the components in two chambers, it is construed as a two part system. Lee teaches “It is an object of the present invention to easily form drug-containing nanoparticles by simply mixing the kit components so that it is easy for the end consumer to use, and drug-containing nanoparticles can be easily formed immediately before use” (Description in English translation). Lee teaches injection solutions that can have buffers and organic acid (English translation). Thus, Lee provides for a formulation with excipient(s).
One of ordinary skill in the art before the time of filing would have provided the separate agents of Pourcelle (peptide portion and copolymer portion) as separate components to be combined before use by the teachings of Lee which provides for a two chamber system to simply mix and form the nanoparticles before use. There would be a reasonable expectation of success to form kits from materials to be conjugated to form targeted nanoparticles by the combined teachings of Pourcelle, van Lith, and Lee. In regard to the amount of nanoparticles delivered, this would be determined by the user for the appropriate drug delivery and treatment through routine optimization. It is noted that Lee teaches solutions that have excipients such as organic acids/buffers as vehicles.
Claim 25 in addition to Claims 1, 3, 5-10, 13-17 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Pourcelle et al (Biomacromolecules, Nov 2007, volume 8, pages 3977-3983); van Lith et al (Bioconjugate Chemistry, 2017, volume 28, pages 539-548) and Tomalia US5714166.
Pourcelle and van Lith teaches the claims as discussed above.
Pourcelle and van Lith do not teach a form of polymer as in claim 25.
Tomalia teaches dendritic polymers (dendrimers) associated with at least one unit of carried material and a conjugate that can have a target director (abstract). Tomalia teaches preferred dendritic polymers are dense star polymers (abstract) and that these have advantageous properties due to their unique characteristics. Tomalia teaches starburst polyethyleneimines (it is a cationic polyelectrolyte) (columns 11-13). Tomalia teaches “STARBURST™ polymers have significant advantages which can provide a means for the delivery of high concentrations of carried material per unit of polymer, controlled delivery, targeted delivery and/or multiple species delivery or use” (Background of the invention).
One of ordinary skill in the art before the time of filing would have incorporated polymers such as Starburst polyethyleneimines into polymer particles of Pourcelle and van Lithe as these are seen as advantageous polymers for conjugate materials and for target directors. Therefore, there was a reasonable expectation of success in using such polymers of the prior art in the teachings of Pourcelle and van Lithe to provide for a two component system where Starburst polymers could be conjugated/attached to moieties such as crosslinkers and targeting polypeptides as taught in Pourcelle and van Lith.
Response to Applicant’s Arguments Over Rejections Involving Pourcelle, van Lith, and Lee
Applicant argues how each of Pourcelle, van Lith and Lee do not teach the claimed invention individually. In these rejections under USC 103, it is a combination of the references that teaches the claimed invention.
Applicant argues that Pourcelle and van Lith require non-specific conjugation in vitro. The claims are to a composition/product and not to a method of using. As Pourcelle and van Lith provide for the claimed components and allow for having them separate before combining, they provide for a two part system as claimed. Claim 1 also indicates that the second component crosslinks the first component at a site of injury, which again relates to the method of use and does not indicate that all such crosslinking is only specific to such a site. As the teachings of Pourcelle and van Lith provide for the claimed components and use of targeting molecules and crosslinkers with polymers and/or nanoparticles, it provides a system where some crosslinking can occur at any site including at a site of tissue injury when applied.
Applicant argues that the claimed composition can circulate as discrete components in the blood stream upon injection. Again, this is toward how the composition is used whereas the claimed composition is examined for components and structures. The prior art only need to teach the components and structure of applicant’s claims to read on the composition.
Applicant argues that the prior art does not provide for hemostasis. Again, this is toward the intended use of the composition and if the prior art teaches the components and structures of the claimed composition, it will read on the claims regardless of what the prior art is used for.
Applicant argues that Pourcelle and van Lith provide for elements that would preclude formation of a crosslinked structure at a site of injury. However, Pourcelle’ s components are separate before they are linked/attached, and thus, would be capable of being kept separate until such conjugation is desired to form the structure. Although the desired utility of Pourcelle and van Lith may be different that using at a site of injury, it remains that it teaches the components and structures of applicant’s claimed composition with two components. Pourcelle does provide for using linkable components and van Lith provides for a click chemistry using DBCO, which provides a crosslink. Thus, there are structures suitable for crosslinking in the prior art.
Applicant argues that Pourcelle, van Lith and Lee do not teach or suggest the goal of hemostasis nor do they provide a structure that can function as a hemostat. Applicant argues that hemostasis is a complex process and their composition provides a non-immunogenic formulation that provides hemostasis. Hemostatic is toward the intended use of the composition/product. As the prior art teaches the components and structure (crosslinking moieties, targeting moieties, polymers and nanoparticles with reactive moieties, solutions with buffers and organic acids (excipients) to carry the components) that would allow for the claimed composition, it meets the limitations. If applicant’s claims were toward a method of use regarding hemostasis at a wound site (site of injury), such a limitation would receive patentable weight. As it stands, crosslinking can occur via a composition motivated by Pourcelle and van Lith at any site where they are combined for the crosslinking reaction. This type of formulation would be capable of various utilities.
Applicant may consider additional compositional components and/or structure that would not be motivated by the prior art and would differentiate from teachings of the prior art.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARK V STEVENS whose telephone number is (571)270-7080. The examiner can normally be reached M-F 9:00 am to 6:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached on (571)272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARK V STEVENS/Primary Examiner, Art Unit 1613
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