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 .
Claim Status
Claims 1, 3, 5-24, 27, 29, 33-34, 36, and 39-40 are pending.
Restriction/Election
Applicant’s election without traverse of Group I (i.e. claims 1, 3, 5-24, 27, and 39-40) in the reply filed May 11, 2026 is acknowledged.
Claims 29, 33-34, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed May 11, 2026.
Applicant’s election without traverse of i) non-racemic mixture of PLA (the polymer) ii) metformin (the metabolic inhibitor) iii) antibiotics (the additional therapeutic agent) iv) bone (the synthetic tissue) in the reply filed May 11, 2026 is acknowledged.
Claims 8-13 and 17-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 11, 2026.
Consequently, claims 1, 3, 5-7, 14-16, 23-24, 27, and 39-40 are under consideration to the extent of the elected invention and species, e.g. non-racemic PLA as the polymer, metformin as the metabolic inhibitor, antibiotic as the additional therapeutic agent, and bone as the synthetic tissue.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/6/2024 has been received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
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.
Claim 5 is 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.
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 5 recites the broad recitation ”between about 0.02 wt% to about 21 wt%”, and the claim also recites ”between about 0.01 wt% and about 13 wt%” 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.
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.
Claims 1, 3, 5-7, 14-16, 23-24, 27, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Co-delivery of metformin and levofloxacin hydrochloride using biodegradable thermosensitive hydrogel for the treatment of corneal neovasularization, Drug Delivery, 26(1): 522-531, published 5/15/2019) in view of Narayanan (Poly(Lactic Acid)-Based Biomaterials for Orthopaedic Regenerative Engineering, Adv Drug Deliv Rev, 107: 247-276, published 4/25/2016) and Nair (Biodegradable polymers as biomaterials, Prog Polym Sci, 32: 762-798, published 6/11/2007).
Liu teaches a biodegradable and bioabsorbable polymeric hydrogel incorporated with both metformin (a metabolic inhibitor of the biguanide class, cf. claims 1, 14-15) and levofloxacin hydrochloride (which is the salt form of the antibiotic levofloxacin, cf. claim 27) designed for thermosensitive in vivo release (abstract). This hydrogel comprises a triblock copolymer of poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-PEG-PLGA), herein referred to as the PLGA polymer (abstract). In order to develop this hydrogel as a carrier for bioactive agents and prepare it with the two drugs metformin and levofloxacin HCl incorporated, Liu teaches the synthesis of the PLGA polymer using commercial starting materials in the presence of a tin catalyst (section 2.2). Following successful synthesis of the polymer, Liu teaches the dissolution of said polymer (0.25 g) into stroke-physiological saline solution (1 mL) (section 2.3). For purposes of explanation, it is important to note that the saline solution used is about 1.00 g/mL, which is an inherent property. In order to prepare the polymer embedded with both drugs, Liu teaches the addition of the 0.25 g dry polymer into the 1 mL saline solution to obtain a 20% polymer/water system (section 2.3). Based on the fact the resultant mixture is a 20% polymer/water system, we can also confirm that the total weight of the composition following polymer addition to the solution is 1.25 g (as
0.25
g
1.25
g
×
100
%
=
20
%
). Following the addition of the polymer into the solution, a given amount of metformin (1, 3, or 5 mg) and levofloxacin HCl (3 mg) were dissolved in the 1 mL polymer solution and homogenized and sterilized (section 2.3). This resulting hydrogel embedded with bioactive agents can be used both in vitro and in vivo with efficacy, as demonstrated by Liu (sections 3.3 and 3.4).
The amount of metformin in the overall hydrogel composition as described by Liu can be stated in various ways. The amount of metformin can be expressed as milligrams, as Liu does in teaching the amount of metformin added to the overall solution. However, this can also be expressed in molarity, as shown below. In order to do so, it must be expressly stated that the molecular weight of metformin is 129.16 g/mol (an inherent chemical property), the density of the saline solution prior to the polymer addition is 1.00 g/mL (an inherent chemical property), the total volume of the saline solution both before and after polymer addition is 1 mL (as the polymer dissolving does not change overall solution volume), and the total weight of the polymer/solution mixture is 1.25 g (as 1 mL of saline solution is equal to 1 g of saline solution, followed by the addition of 0.25 g of dry polymer).
When looking at the inclusion of 1 mg of metformin into the hydrogel solution, the amount of metformin can be expressed as a concentration via molarity (mM), as demonstrated below:
m
i
l
l
i
m
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s
o
f
m
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t
f
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m
i
n
=
m
a
s
s
m
o
l
e
c
u
l
a
r
w
e
i
g
h
t
=
1
m
g
129.16
m
g
/
m
m
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l
=
0.0077423
m
m
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l
m
M
m
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t
f
o
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m
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n
=
m
m
o
l
L
=
0.0077423
m
m
o
l
0.001
L
=
7.7423
m
M
This shows that 1 mg of metformin added to the solution results in a solution with a metformin concentration of 7.7423 mM (cf. claims 1, 3, 39).
Further, we can demonstrate the amount of metformin as a weight percentage of the overall composition, as demonstrated below:
w
t
%
m
e
t
f
o
r
m
i
n
=
m
g
m
e
t
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m
g
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l
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t
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×
100
%
=
1
m
g
1.25
g
×
100
%
=
1
m
g
1250
m
g
×
100
%
=
0.08
w
t
%
This shows that 1 mg of metformin added to the solution results in a solution with a metformin weight percentage of 0.08 wt% (cf. claims 1, 5, 16, 39).
However, Liu is silent regarding the use of non-racemic mixture of polylactic acid/PLA, as the polymer for the hydrogel as elected by Applicant.
This deficiency is made up for by the teachings of Narayanan and Nair.
Narayanan teaches a bioengineered scaffold that comprises poly(lactic acid) (PLA)-based biomaterial that can be beneficial when applied to orthopaedic regenerative engineering (abstract). PLA-based materials are extensively used as implantable devices such as screws, pins, washers, darts, and arrows (introduction par. 5). Narayanan teaches the benefits of using PLA-based material, as it is biodegradable and biocompatible, and further teaches that it may be a component of copolymer materials such as PLGA (introduction par. 4). Copolymerizing PLA with other related monomers to develop a copolymer material such as PLGA allows tunability of the overall biomaterial (introduction par. 4). Narayanan also teaches that PLA has chirality, as the monomers may either be D-lactic acid or L-lactic acid (introduction par. 3). These monomers can be used to develop chiral pure polymers or racemic polymers, depending on if the monomers used are pure D or pure L, or a mixture thereof. Narayanan teaches that selection of the monomers is crucial. For example, polymers derived exclusively from L-lactic acid (PLLA) degrades in 2-5 years, whereas a racemic polymer derived from both D and L-lactic acid (PDLLA) “loses strength in less than 2 months, and completely degrade[s] within 12 months” (introduction par. 3). This trend carries over to copolymers as well, wherein chiral pure PLA polymers are more structurally sound and stronger than copolymers such as PLGA. The differences in biomaterial properties based on the monomer selection makes PLA and related polymeric materials attractive for biomedical applications. One such biomedical application as taught by Narayanan is in producing scaffolds for bone regeneration. When compared to other potential biocompatible materials, such as collagen or ceramics, PLA-based material has ideal processability and little brittleness, as well as high mechanical strength (section 4(ii) par. 2). The PLA-based material can be fashioned into scaffolding to promote bone regeneration (cf. claim 40). Not only does PLA-based material impart these benefits, but Narayanan further teaches that bioactive materials can be incorporated into the matrix to promote tissue regeneration (section 4(ii) par. 9).
Nair teaches various potential polymers that can be used for biomaterials. In particular, Nair teaches that degradable polymeric biomaterials are ideal for developing therapeutic devices (abstract). Nair continues to state that each particular application requires a specific material with specific physical, chemical, biological, biomechanical and degradation properties to be efficient. In particular, polylactides are useful as they exist in two chiral forms, resulting in their ability to form semi-crystalline polymers (section 3.1.2). PLA can exist in the pure form of the chiral molecule (PLLA when completely L-enantiomer), a fully racemic form (i.e. 50/50 D to L), or non-racemic mixture (PDLLA). Nair teaches the PDLLA is an amorphous polymer due to the “random distribution of L- and D-lactide units” (i.e. random mixture other than 50/50) (section 3.1.2). Nair states that PDLLA (i.e. a non-racemic mixture) is “a preferred candidate for developing drug delivery vehicles and as low strength scaffolding material for tissue regeneration” (section 3.1.2).
It would have been prima facie obvious to one skilled in the art before the effective filing date of the instant application to produce the hydrogel as taught by Liu with the PDLLA polymer as taught by Narayanan and Nair. One of ordinary skill in the art would have been motivated to modify the polymeric makeup of the hydrogel as taught by Liu with a non-racemic form of PLA, such as PDLLA, as taught by Narayanan and Nair as it has been shown in the art and described by Narayanan and Nair that PLA in general has greater strength and durability compared to a copolymer such as PLGA (as taught by Narayanan) and PDLLA (i.e. non-racemic mixture) is ideal for drug delivery and tissue regeneration (as taught by Nair). One would have a reasonable expectation of success as it is known in the art that hydrogels can comprise various types of monomers, and PDLLA and PLGA are both members of the same class of monomers. Further, hydrogels derived from both kinds of monomer can be associated with bioactive molecules, as explained by both Liu and Narayanan.
The resulting composition as taught by both Liu, Narayanan and Nair would comprise a non-racemic mixture of poly(lactic acid) hydrogel (such as PDLLA, non-racemic mixture, cf. claims 1, 6, 7, 39) as it is known in the art that PDLLA polymers have better physical and chemical properties for drug delivery and tissue regeneration (as taught by Nair), combined with metformin and levofloxacin HCl in a predetermined amount. As described above, this predetermined amount can be based on the teachings of Liu (i.e. 1 mg metformin and 3 mg levofloxacin HCl). When incorporating metformin in this amount, metformin is present in a concentration of about 7.7 mM, or about 0.08 wt%. This composition reads on instant claim 1, as the polymer, metabolic inhibitor (i.e. metformin as elected by Applicant), and amount therein is taught in the prior art. Therefore, claim 1 is rejected.
The overall amount of metformin can be expressed in various ways (i.e. concentration, wt%). As described supra, 1 mg metformin is equivalent to 7.7 mM in the composition as taught by Liu. This falls within the range as claimed in claim 3. Therefore, claim 3 is rejected. 1 mg metformin is also equivalent to 0.08 wt% in the composition as taught by Liu. This falls within the range as claimed in claims 5 and 16. Therefore, claims 5 and 16 are rejected.
The polymer selected in the composition is ideally PLA, and further a non-racemic version of PLA (i.e. PDLLA), given the benefits described supra. This reads on instant claims 6 and 7. Therefore, claims 6 and 7 are rejected.
As taught by Liu, metformin can be incorporated into a hydrogel such as the one as taught by Narayanan and Nair. Therefore, claims 14 and 15 are rejected.
The method of manufacturing the polymer along with the selected drugs as taught by Liu results in the metabolic inhibitor and antibiotic being incorporated into the polymer. This is demonstrated by the slurry formation and homogenization of the mixture as described supra. Therefore, claim 23 is rejected. Narayanan teaches further that polymeric scaffolds can also be coated with bioactive materials, such as antibiotics (section 2(i) par. 4). As metformin is a bioactive material, it follows that it can be coated onto the polymer itself as Narayanan describes. Therefore, claim 24 is rejected.
Liu’s composition includes levofloxacin HCl, as described supra. As levofloxacin HCl is the salt form of the antibiotic levofloxacin, claim 27 is rejected.
Narayanan describes how these polymeric biomaterials can be used as scaffolding for synthetic tissue, and explains the benefits regarding bone tissue regeneration. As this synthetic tissue consists of the polymer and metformin in the amount as described supra, and further is taught in relation to bone tissue regeneration, claims 39 and 40 are rejected.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5-7, 14-16, 23-24, 27, and 39-40 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 12-14, 21-22, 25, 27, 29-30, and 35-36 of copending Application No. 18833739 in view of Nair (Biodegradable polymers as biomaterials, Prog Polym Sci, 32: 762-798, published 6/11/2007).
Claims 1, 3, 5-7, 14-16, 23-24, 27, and 39-40 of the instant application recite a composition comprising a polymer and a metabolic inhibitor wherein the inhibitor is of the biguanide class and specifically is metformin, which may also comprise an additional bioactive agent such as an antibiotic. The polymer in the instant case is a non-racemic mixture of PLA. The non-racemic PDLLA can either be infused or coated with a bioactive material with a specific amount of between about 0.01 to about 11 wt%, as described supra. The inventive concept in general is regarding the inclusion of metformin and an antibiotic into a PDLLA non-racemic polymer that can then be used as scaffolding for bone tissue regeneration.
Claims 1, 3, 5, 12-14, 21-22, 25, 27, 29-30, and 35-36 of copending application ‘739 recite a composition comprising a polymer and a metabolic inhibitor wherein the inhibitor may be of the biguanide class and specifically metformin, which may also comprise an additional bioactive agent such as an antibiotic. The overall amount of metformin in the composition mirrors that of the instant claims as well. Further, the composition can be used for tissue regeneration as well. However, ‘739 does not recite the use of non-racemic mixture of PLA.
This is made up for by the teachings of Nair.
Nair has been described supra.
Instant claims 1, 3, 5-7, 14-16, 23-24, 27, and 39-40 are obvious variants of claims 1, 3, 5, 12-14, 21-22, 25, 27, 29-30, and 35-36 of copending application ‘739 because it would have been prima facie obvious to use the non-racemic version of PLA such as PDLLA as taught by Nair as the polymer of the ‘739 composition because Nair teaches that a non-racemic mixture of PDLLA is the premier choice of biodegradable polymer for drug delivery methods and tissue regeneration (see Nair secion 3.1.2), and the claimed composition of the ‘739 claims is for a synthetic tissue or drug depot.
Although the claims at issue are not identical, they are obvious variants because they recite the same components of the composition in identical amounts with the exclusion of the specific polymer, which is made up for by the Nair.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 5-7, 14-16, 23-24, 27, and 39-40 are directed to an invention not patentably distinct from claims 1, 3, 5, 12-14, 21-22, 25, 27, 29-30, and 35-36 of commonly assigned copending Application No. 18833739. Specifically, see above.The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned copending Application No. 18833739 discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW RYAN BURKE whose telephone number is (571)272-8949. The examiner can normally be reached Mon-Fri. 8am-5pm.
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/MATTHEW RYAN BURKE/Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
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