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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11 Nov, 2025 has been entered.
Election/Restrictions
Applicants elected fracture non-union without traverse in the reply filed 4 June, 2018.
Claims Status
Claims 21, 23-27, 38-42, 46, 48, and 49 are pending.
Claims 21, 38, 41, 42, 46, and 49 have been amended.
Claims 24-27 have been withdrawn from consideration due to an election/restriction requirement.
Maintained/Modified Rejections
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 21, 23, 38-42, 44, 46, 48, and 49 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Bukata et al (Curr. Osteoporos. Rep. (2010) 8 p38-33) in view of Kidron et al (US 20110142800, previously cited), Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720, previously cited), and Hammerle et al (Bone (2012) 50 p965-973).
Bukata et al discuss orthopedic uses of teriparatide (title) in disorders beyond osteoporosis (abstract). This compound has proved useful in treating non-union or delayed union not associated with osteoporosis (p28, 2nd column, 2nd paragraph, continues to p29). A number of examples were given of using this therapy to treat fractures, some of which were not associated with osteoporosis (p31, 1st column, 2nd paragraph), with some discussion on when it will be effective (p31, 2nd column, 1st paragraph).
The difference between this reference and the instant claims is that this reference does not specify formulations with SNAC or the claimed pharmacokinetics.
Kidron et al discuss compositions for the oral administration of proteins (title), including parathyroid hormone (paragraph 33). Using oral dosing, the low patient compliance with injected dosage forms can be avoided (paragraph 2). This is accomplished using a protease inhibitor and an absorption enhancer (paragraph 13). The protease inhibitor can be soybean trypsin inhibitor (paragraph 50), applicant’s elected species of protease inhibitor. The absorption enhancer can be SNAC (paragraph 65). Various dosage forms, including tablets, are discussed (paragraph 120). Magnesium stearate, applicant’s elected lubricant, is mentioned as useful for that purpose (paragraph 114). The composition can be formulated to achieve a particular release profile, as known by one skilled in the art (paragraph 115). A wide range of concentrations of the adsorption enhancer can be used (paragraph 68), and the amount of both the absorption enhancer and the protease inhibitor can be optimized (paragraphs 128 and 129). This reference teaches oral dosing of polypeptide drugs using SNAC.
Le Tourneau et al discuss dose escalation methods for phase I clinical trials (title). The main goal of the phase I clinical trial is to establish the recommended dose and/or dose schedule of new drugs or drug combinations for phase II trials (abstract). The optimization goal is to avoid unnecessary exposure of patients to subtherapeutic doses of an agent while preserving safety and maintaining rapid accrual (p708, 1st column, 2nd paragraph), i.e. to optimize for efficacy and safety. This reference teaches methods for optimizing the dose and dose schedule for pharmaceutical agents.
Hammerle et al discuss a clinical trial examining the pharmacokinetics of orally administered teriparatide with an absorption enhancer (abstract). Dosages between 1 and 10 mg of teriparatide using 200 mg of CNAC (structurally very similar to SNAC of the instant claims), and 2.5-5 mg using 200 mg of CNAC were used (p967, 1st column, last paragraph, continues to 2nd column). Pharmacokintics data shows generally increasing blood concentrations with dose, and similar timing of uptake and no significant differences between the 100 and 200 mg CNAC arms (table 2, p969, top of page). Note that the Cmax (74.1-1624 pg/mL) and AUC/Cmax (0.386-0.449h) from table 2 are mostly in the range claimed by applicants, and that the Cmax of the more standard administration route was 149 pg/ml (table 2, p969, top of page). In other words, the dosages used were within the range of the therapeutic dosages, however, uncertainty is very large in all measurements. While the ratio of AUC/Cmax is slightly higher than claim 42, it is not clearly statistically different. This reference shows that the pharmacokinetics claimed by applicants is similar to the known pharmacokinetics for a similar material.
Therefore, it would be obvious to use the formulations of Kidron et al for the therapies of Bukata et al, to increase the compliance rate compared to injected dosage forms by using an oral dosage form. As Kidron et al teaches these compositions for parathyroid hormone, a genus that includes the teriparatide of Bukata et al, an artisan in this field would attempt this formulation with a reasonable expectation of success.
Furthermore, it would be obvious to optimize the dose and dose schedule for the materials, to generate the optimum response from patients, considering efficacy and toxicity, as described by Le Tourneau et al. As every therapy approved for humans (and many more that were not) has gone through this process, an artisan in this field would attempt it with a reasonable expectation of success.
Bukata et al discuss using teriparitide to treat fracture non-union. Kidron et al discuss using SNAC formulations for oral dosage forms, including tablet forms, with soybean trypsin inhibitor. Note that differences in concentration are not considered a patentable distinction (MPEP 2144.05(II)(A)). Hammerle et al show that the pharmacokinetics claimed by applicants are, within the error of the measurement, what would be expected. Thus, the combination of references renders obvious claims 21, 23, 41, and 42.
Le Tourneau discuss optimizing the dose schedule, rendering obvious claims 38-40.
Kidron et al discuss a range of concentrations for the absorption enhancer, therapeutic, and protease inhibitor, which cover all the ratios of claims 46. Alternatively, the courts have ruled that differences in concentration are not sufficient to lend patentability to subject matter encompassed by the prior art absent secondary considerations (MPEP 2144.05(II)(A)). Thus, the combination of references renders obvious that claim.
Kidron et al discuss using magnesium stearate, a lubricant, rendering obvious claims 48 and 49.
response to applicant’s arguments
Applicants argue that there is no reasonable expectation of success, that Kidron et al discusses insulin and exenatide, not teriparatide, that it is not possible to get to applicant’s invention via optimization of Kidron et al, that SNAC and CNAC would not be expected to give similar pharmacokinetics, that Hammerle et al teaches away from the invention, claim an unexpected result of variation of SNAC concentration provide improved bioavailability, claim an unexpected result of the claimed formulation suitable for use, and claim an unexpected result of reduced bone resorption. These arguments are supported by a declaration by Prof. Greg Burshtein, applicant.
Applicant's arguments filed 20 Nov, 2025 have been fully considered but they are not persuasive.
Applicants argue that there is no reasonable expectation of success, based on a reference published after applicant’s priority date discussing the difficulties in oral peptide availability and Prof. Burshtiein’s failed experiments with other polypeptide drugs. For the reference, it is not clear what an expectation of success is based on the reference; note that applicants have demonstrated very low bioavailability and a large amount of variability (based on the large standard deviations of their experiment). Furthermore, Hammerle et al demonstrate success in getting physiologically relevant amounts into the bloodstream using a method vary similar to applicants. Applicants argue that the inventors have failed with other peptide drugs. However, it’s not clear what applicants consider a ‘success,’ it’s not clear how many different polypeptide drugs applicants have attempted to develop, it’s not clear if the data given is after optimization or not, it’s not clear if this data was developed just for this invention to show unpredictability. The MPEP states that the failure of experimenters who have no interest in succeeding should not be accorded great weight (MPEP 716.07). Nor is it clear that it would be expected for these polypeptide formulations to succeed. It’s known in the art that SNAC works by weakly binding to the peptide, rendering it temporarily more hydrophobic, which allows it to more easily diffuse across gastrointestinal barriers (Malkov et al, Curr. Drug Deliv. (2005) 2 p191-197, p197, 1st column, 2nd paragraph). Logically, more hydrophobic peptides would benefit less, as they are already hydrophobic. But we do not know what peptides applicants failed with.
Applicants argue that Kidron et al discusses insulin and exenatide, not teriparatide. While the examples are directed to those two drugs, the disclosure of the reference is much broader, and explicitly mentions parathyroid hormone, a genus that includes teriparatide.
Applicants argue that it is not possible to get from Kidron et al to applicant’s invention. The reason is that the examples use a lower ratio of SNAC/peptide, and that the reference does not discuss ratios. However, the disclosure of Kidron et al is broader than just the examples, and allow for larger amounts of SNAC (MPEP 2123(I)). Applicants note that Kidron et al does not describe their invention in terms of ratios, as applicants do, but any formulation will have a ratio of SNAC and therapeutic. The fact that Kidron et al does not discuss their invention in those terms does not mean that optimization will not end up with similar values.
Applicants argue that SNAC and CNAC would be expected to give different pharmacokinetics. CNAC has the structure
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. SNAC has the structure
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. The ONLY difference is the chloride on CNAC that is not found on SNAC. Compounds with similar structures are expected to have similar properties (MPEP 2144.09(I)). These two compounds have similar structures, and are used for the same purpose. A person of skill in the art would expect them to work by a similar mechanism – weak absorption onto the therapeutic, increasing its lipophilicity to increase absorption from the digestive tract (Malkov et al, Curr. Drug Deliv. (2005) 2 p191-197). Applicants point to other differences in effect, but they do not say anything about the mechanism of uptake.
Applicants argue that Hammerle et al teaches away from the invention. This requires a mathematical transformation not suggested by any reference in the rejection, nor have applicants pointed to any prior art reference suggesting the transformation. It is not clear how this is a teaching away.
Applicants argue that increasing the ratio of SNAC to teriparatide increases bioavailability, an alleged unexpected result. There are a number of issues with the data underlying the argument. First, as the amount of SNAC is varied, the difference is made up with sodium starch glycolate, which applicants state can potentiate SNAC activity (paragraph 28 of Prof. Burshtein declaration). In other words, the different doses are not an apples to apples comparison. Second, applicants have previously demonstrated that varying the amount of SNAC can affect dissolution (declaration of 4 March, 2021). It is not clear if applicants have optimized their tableting procedure for each formulation for optimum dissolution; the results applicants are demonstrating could just be differences in this parameter due to insufficient optimization. Third, it is the burden on applicants to show that the results are statistically significant (MPEP 716.02(b)). There is no mention of statistical significance in the declaration, but the means±SD overlap for most of the comparisons, strongly suggesting a lack of statistical significance. Finally, it is not clear why this is considered unexpected. The only evidence that applicants have given that a person of skill in the art would assume otherwise is an experiment of Hammerle et al, which has large error bars. But, Hammerle et al does not say that the concentration of absorption enhancer has no effect, just that it was not measured over a small range – if it was over all concentrations, it would have no effect and could be left out of the formulation. Furthermore, the mechanism of action is weakly binding to the protein to make it more lipophilic so it will diffuse out of the gastrointestinal tract and increase protease resistance (Malkov et al, Curr. Drug Deliv. (2005) 2 p191-197, p197, 1st column, 2nd paragraph). Given that this is a binding, it can be saturated, and a person of skill in the art would also appreciate that the soybean trypsin inhibitor, also a protein and included in a large excess over the therapeutic, would also be bound, requiring more of the absorption enhancer to saturate. In other words, a person of skill in the art would expect a non-linear saturable effect of varying the amount of SNAC.
Applicants argue that the formulation works is unexpected, and that it has superior pharmacokinetics over SC administration, as it has faster uptake. It is not clear how a formulation working much as the rejection suggests is unexpected. But it is known that SC administration leads to relatively slow uptake (Richter et al, Drug Metab. Dispos. (2014) 42 p1881-1889, abstract), and oral uptake can be rapid (Teja-Isavadharm et al, Br. J. Clin. Pharmacol. (1996) 42 p599-604, cited by applicants).
Finally, applicants argue that the formulation unexpectedly leads to lower bone resorption. Applicants have stated (declaration of 20 Nov, 2025) that it is known in the art that intermittent high doses leads to increase in bone mass, while prolonged exposure leads to resorption (paragraph 50). So the more rapid oral uptake compared to the slow SC uptake would be expected to produce this effect. In addition, it is not clear if this is different than the closest prior art (MPEP 716.02(e)), which does not specify the administration route, or if it is statistically significant compared to the SC administration (MPEP 716.02(b)(I)).
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
first rejection
Claims 21, 23, 38-42, 46, 48, and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 32 of copending Application No. 15/549394 (US 20180036382) in view of Bukata et al (Curr. Osteoporos. Rep. (2010) 8 p38-33) and Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720).
Competing claim 1 describes tablet compositions comprising SNAC, teriparatide, and soybean trypsin inhibitor for oral administration with specific dosages and pharmacokinetics, while competing claims 2 and 3 give more details of the pharmacokinetics, which are similar to that of the instant claims. Competing claim 32 describes using these formulations to treat disorders for which the therapeutic is appropriate.
The difference between the competing claims and the instant claims is that the competing claims do not discuss fractures and bone defects.
Bukata et al discuss orthopedic uses of teriparatide (title) in disorders beyond osteoporosis (abstract). This compound has proved useful in treating non-union or delayed union (p28, 2nd column, 2nd paragraph, continues to p29). A number of examples were given (p31, 1st column, 2nd paragraph), with some discussion on when it will be effective (p31, 2nd column, 1st paragraph).
Le Tourneau et al discuss dose escalation methods for phase I clinical trials (title). The main goal of the phase I clinical trial is to establish the recommended dose and/or dose schedule of new drugs or drug combinations for phase II trials (abstract). The optimization goal is to avoid unnecessary exposure of patients to subtherapeutic doses of an agent while preserving safety and maintaining rapid accrual (p708, 1st column, 2nd paragraph), i.e. to optimize for efficacy and safety. This reference teaches methods for optimizing the dose and dose schedule for pharmaceutical agents.
Therefore, it would be obvious to use the formulations of the competing claims for the treatment of fracture non-union, as Bukata et al teach that the active ingredient is useful for that purpose. As the competing claims explicitly state that the formulations are used to treat appropriate conditions, an artisan in this field would administer these formulations with a reasonable expectation of success.
Furthermore, it would be obvious to use the methods of Le Tourneau to optimize the dose and dose schedule of the drug to maximize efficacy. As this is done for any drug that goes into humans, an artisan in this field would attempt this process with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments:
Applicants request that this rejection be held in abeyance until allowable subject matter is identified. However, until the rejection is overcome, it will remain valid.
second rejection
Claims 21, 23, 38-42, and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-9 and 13 of US patent 10,010,503 in view of Bukata et al (Curr. Osteoporos. Rep. (2010) 8 p38-33) and Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720).
The teachings of the competing claims and other references cited are similar to those of the first obvious type double patenting rejection, and the logic is similar.
response to applicant’s arguments:
Applicants request that this rejection be held in abeyance until allowable subject matter is identified. However, until the rejection is overcome, it will remain valid.
third rejection
Claims 21, 23, 38-42, 46, 48, and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 16, and 42 of copending Application No. 15/549425 (US 20180028622) in view of Bukata et al (Curr. Osteoporos. Rep. (2010) 8 p38-33) and Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720).
The teachings of the competing claims and other references cited are similar to those of the first obvious type double patenting rejection, and the logic is similar.
response to applicant’s arguments:
Applicants request that this rejection be held in abeyance until allowable subject matter is identified. However, until the rejection is overcome, it will remain valid.
fourth rejection
Claims 21, 23, 38-42, and 46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18 and 28 of U.S. Patent No. 12,239,691 in view of the discussion of drug dosage on the web page drugs.com (www.drugs.com/dosage, available 2010), Bukata et al (Curr. Osteoporos. Rep. (2010) 8 p38-33) and Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720).
Competing claim 18 describe a method of treating a disorder treatable by oral administration by administering a drug in an oral dosage form with an absorption enhancer, including NAC, considered equivalent to the sodium salt claimed by applicants. Competing claim 28 gives teriparatide as the drug.
The difference between the competing claims and the instant claims is that the competing claims do not specify certain effects and parameters, and does not require a tablet form.
The webpage Drugs.com gives tablets as a common dosage form, rendering that mode of administration obvious. The teachings of Bukata et al and Le Tourneau et al were given above, as well how they combine with the competing claims to render the instant claims obvious.
response to applicant’s arguments:
Applicants request that this rejection be held in abeyance until allowable subject matter is identified. However, until the rejection is overcome, it will remain valid.
fifth rejection
Claims 21, 23, 38-42, and 46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 9, and 10 of U.S. Patent No. 12,076,373 in view of Bukata et al (Curr. Osteoporos. Rep. (2010) 8 p38-33) and Le Tourneau et al (J. Natl. Cancer Inst. (2009) 101 p708-720).
The teachings of the competing claims and the logic of the rejection follow the previous rejections for double patenting, and will not be repeated here.
response to applicant’s arguments:
Applicants request that this rejection be held in abeyance until allowable subject matter is identified. However, until the rejection is overcome, it will remain valid.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658