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 .
Status of the Application
The amendment and remarks of 20 November 2025 are entered.
Claims 2, 5, 8, 15, 19, 20, and 22-27 have been canceled. Claims 1, 3, 4, 6-7, 9-14, 16-18, 21, and 28-39 are pending. Claims 3, 4, 21, 30, and 31 are withdrawn without traverse. Claims 1, 6-7, 9-14, 16-18, 28-29, and 32-39 are being examined on the merits.
The rejection of claims 1, 6-7, 9-14, 16-18, and 28-29 under 35 U.S.C. 112(a) as lacking written description is modified and maintained, with the Examiner’s response found below.
The rejection of claims 32 and 33 under 35 U.S.C. 103 as being unpatentable over ‘863 is modified and maintained, with the Examiner’s response found below.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6-7, 9-14, 16-18, 28-29, 32, and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The amended claims introduce the limitation that the compositions containing a linear or cyclic peptide drug of 1 kDa to 5 kDa and an excipient with a pKa>12 are such that “the constitution of the pharmaceutical composition is such that, if the pharmaceutical composition is added to 10 ml of 0.1 M aqueous sodium bicarbonate solution, the pH of the solution will be higher than pH 9”. Claim 29 has a similar amendment except that the composition contains arginine HCl instead of the more generic excipient with a pKa>12 as in claim 1. Claim 32 requires a pharmaceutical composition, implying therapeutic action, having a peptide of 1-5 kDa, arginine free base or arginine HCl, in tablet form for oral-gastric administration, not having an enteric coating and not having more than one peptide.
This amendment describes the composition largely by function, i.e. having a specific property when reconstituted in specific conditions, rather than by specific structure. The claims are very broad with respect to the underlying protein or peptide drug, and at the broadest reasonable interpretation of the generic claim there are no limits to what proteins or peptides might be considered as part of the claimed invention. The excipient is narrower as being directed to arginine free base, EDTA tetrasodium salt, trisodium phosphate, tris(hydroxymethyl)aminomethane, lysine, and calcium hydroxide.
Claim 32 implies function by claiming as a pharmaceutical. This is a broad genus of peptides within the limitations, with no clear knowledge a priori if a peptide of 1-5 kDa has any sort of therapeutic function when administered alone or in combination with arginine free base or arginine HCl.
An examination of the specification indicates that the functional language in the claims occurs only once at p.25 lines 31-35. Further analysis of the specification indicates that while Examples 1 and 2 show the advantages of such a formulation in terms of proteolytic stability, in neither Example are 10 ml formulations made having a pH of 9 or greater. Example 1 places PTH(1-34) in simulated gastric fluid containing pepsin, where 0.5 mg/ml PTH(1-34) is combined with L-Arg, L-Arg HCl, Zn arginate chelate, SNAC, or SNAC+L-Arg (see e.g. Table 1). Only those formulations with L-Arg showed prevention of pepsin digestion, while zinc arginate chelate had partial protection against digestion. Example 2 shows PTH(1-34) with L-Arg prevents trypsin digestion while L-Arg HCl allows for higher levels of trypsin digestion (see e.g. Table 2).
No examples actually show any pharmaceutical compositions being formed such that they have a pH of 9 or higher when formulated in 10 mL 0.1 M NaHCO3.
The only examples pertaining to claim 32 are of limited peptide species.
The claims as written offer a functional limit without any real guidance from the specification on the structure-function correlation required to determine a priori whether a given protein or peptide drug combination with an excipient of arginine free base, EDTA tetrasodium salt, trisodium phosphate, tris(hydroxymethyl)aminomethate, lysine, and calcium hydroxide; or with Arg-HCl would have the required pH after constitution in the claimed conditions. The claims and specification require a specific structure-function relationship while leaving all effort to determine said structure-function correlation on the part of the skilled artisan.
Concerning claim 32, the species are of limited scope compared to the genus of a linear or cyclic 1-5 kDa peptide, with no clear knowledge that they necessarily possess therapeutic action in order to be a pharmaceutical composition. Others such as adalimumab and infliximab are well beyond the claimed size limit (see e.g. Examples 13 and 20). Semaglutide as in Examples 16-18 fits within the limit, but again this is not representative of the broad linear or cyclic 1-5 kDa genus. Collectively, a limited number of species of 1-5 kDa peptides as pharmaceutical compositions were possessed by Applicants and are not representative of the genus.
Considering the claims and the disclosure as filed, one of ordinary skill in the art would not be able to readily identify a representative number of species from the claimed species that satisfy the claimed function. Even considering Examples 1 and 2, there is no reasonable conclusion from the disclosure that the PTH(1-34) formulations have the claimed function. Even assuming arguendo that those formulations have the required pH after reformulation, they represent single formulations from a broadly claimed genus. There is no reasonable expectation that any and all linear or cyclic peptide drugs of 1-5 kDa if combined with the claimed excipients or Arg-HCl necessarily result in the claimed pH. At best, single compounds are disclosed having the claimed function that are not representative of the broadly claimed genus. The onus is left almost entirely on the skilled artisan to make and test the required combinations and determine if the functional properties are present in the resultant formulation. There would not be a conclusion that Applicants were in possession of the claimed genus through representative numbers of species.
The limited species as disclosed similarly do not represent the genus of claim 32, even if it has a different required function as compared to claim 1. While the species disclosed are functional peptides, they are not necessarily representative of the genus of linear or cyclic 1-5 kDa peptides, which is very diverse. Mere disclosure of limited species from a broad genus is insufficient to demonstrate written description. See MPEP 2163 II. A. 3. (a) ii).
Accordingly, the Examiner finds that written description is lacking.
Response to Arguments:
The Applicants summarize the rejection of record.
The Examiner finds no material issues with the summary as provided.
The Applicants argue the claims have been amended to recite a linear or cyclic peptide drug of 1 to 5 kDa such that the genus has been significantly narrowed and the exemplified species are representative of the genus as claimed.
The Examiner disagrees. By necessity a peptide must be linear or cyclic, such that the amendment specifying such does not materially distinguish from the previous claim to just a peptide drug. Similarly, it is not clear how recitation of a peptide only instead of a protein materially narrows the genus, since any proteins that are within the previous weight range are by necessity also peptides. The narrowing of the range from 1-6 kDa down to 1-5 kDa does narrow the genus, but still provides for a broad range of potential peptide drugs to be species within an expansive genus. The “comprising” language further leaves the peptide drugs open-ended so that the 5 kDa limit is not truly a limit on the size of a given peptide to still read upon the claims. As argued previously and in the rejection of record, only a highly limited number of actual peptides within the 1-5 kDa range are exemplified in the specification and would not be viewed by one of ordinary skill in the art as representative of the full breadth of the genus as claimed. There is no clear structure implied by the claims, and the disclosed and exemplified species are PTH(1-34), semaglutide, and octreotide. Three species from a genus defined largely by function rather than structure does not demonstrate possession of the genus.
The Applicants argue the application addresses a need for effective, shelf-stable, and safe compositions for non-invasive delivery of peptide drugs.
The Examiner agrees the application may address a need, but such considerations are not of any particular relevance to the consideration of written description. Even allowing for this, the Examiner argues the examples as disclosed still show a highly limited number of species meeting this requirement that are not representative of the broad genus as claimed.
The Applicants argue the invention is not meant to be limited to any particular peptide species but rather that the specification and knowledge in the art would lead to other peptides of similar size and structure as being applicable in the claimed invention. The Applicants argue disclosure of more species as on p.4 and other sections of the specification.
The Examiner does not dispute that the goal of the claims is to encompass peptides in general with a particular size and general structure. The Examiner disagrees that the disclosure as filed provides support for this claiming. Again, only limited species are disclosed as reduced to practice. Those are presumed to have the required function but it is not readily clear that they offer the correct pH if reconstituted in 10 ml of 0.1 M aqueous sodium bicarbonate. Allowing for the examples as provided to meet this limitation is still a highly limited number of species from an expansive genus of peptides and excipient combinations. Furthermore, it can be argued that there is not clear evidence that any peptide and excipient combination necessarily can be administered transmucosally as claimed. Other species are generally disclosed in the specification but again it is not clear that they possess the required function as claimed.
The Applicants argue the claims satisfy the functional language. The Applicants argue written description is satisfied if the skilled artisan can determine whether or not a pharmaceutical composition or method is within the scope of the claims. The Applicants argue this standard is met by the instant claims because the steps are set within the specification for one of ordinary skill in the art to determine if they are working within the scope of the claim. The Applicants argue one of ordinary skill in the art merely has to test a composition by placing it in 10 ml of 0.1 M aqueous sodium bicarbonate and measure the pH. The Applicants argue the test is straightforward and does not present undue difficulties. The Applicants argue this is true in light of the excipient requirements and definition of the peptide drug, and argue there is no basis for maintaining the written description rejection.
The Examiner disagrees. The basis for written description is not whether or not one of ordinary skill in the art can determine if a composition or method reads upon a claim. Per MPEP 2163 II. 2., “The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated that the inventor was in possession of the claimed invention.” See also MPEP 2163 II. A. 3. (a) ii), stating “See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").” Nothing in MPEP 2163 indicates that the basis for written description is whether one of ordinary skill in the art can determine if a composition or method reads upon a claim. Rather, such an analysis of claims is more appropriate for determining compliance with 35 U.S.C. 112(b). The Examiner agrees that a process exists for determining compliance, but the breadth of the claims is still so expansive that it is not merely a matter of routine experimentation to ensure compliance since there are only broad structures and functional requirements within the claim. Additionally, as argued in the rejection of record there are highly limited disclosed species that read upon the genus, further calling into question whether the full scope the genus was possessed by Applicants. The Examiner contends that the full scope was not possessed as argued in the rejection of record.
The Applicants point to the previous Declaration of Dr. Florian Föger, including the data as found in Exhibit A.
The Examiner argues that the Declaration and accompanying data in Exhibit A were previously considered and not found to be persuasive to demonstrate written description of the genus as claimed. Even considering the narrower genus encompassed by the amended claims, the Examiner is not persuaded that the experiments of Exhibit A show a representative number of species sufficient to demonstrate written description of the claimed genus.
The Applicants argue it follows from the PTH(1-34) experiments of the Declaration that other species of linear or cyclic peptides having a weight range of 1-5 kDa would be predictable.
The Examiner disagrees. The PTH(1-34) experiments offer no predictability that any linear or cyclic peptide of 1-5 kDa when placed in the claimed excipients necessarily has the function as claimed. Again, the Applicants offer limited examples and leave any and all further testing on the part of the skilled artisan. The Examiner disagrees that the data offers predictability to any member of the genus based on a single peptide species and limited excipient combinations.
The Examiner has considered the Applicants’ arguments but not found them persuasive. The rejection is modified in light the amendment and maintained.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 32-37 are rejected under 35 U.S.C. 103 as being unpatentable over Stern and Consalvo (US 8,377,863 B2, published 19 February 2013, hereafter referred to as ‘863).
The ‘863 patent discloses a dosage form for oral delivery comprising a peptide and coated acid particles (see e.g. claim 1). The acid can be a salt of an amino acid (see e.g. claim 10). The active peptide includes calcitonin, PTH, PTH truncates, and amidated PTH truncates (see e.g. claim 12). The composition can be compressed into a tablet (see e.g. claim 16).
The difference between ‘863 and the claimed invention is that ‘863 does not explicitly disclose a formulation with arginine free base or arginine HCl.
However ‘863 discloses acid salts of amino acids are generally hydrochlorates, and lists arginine as one option, i.e. Arg-HCl (see e.g. Col.10 lines 47-57).
It would have been obvious to one of ordinary skill in the art to prepare an oral formulation compressed into a tablet comprising a peptide selected from calcitonin, PTH, PTH truncates, and amidated PTH truncates and a coated acid selected from Arg-HCl. The rationale is an “obvious to try” type rationale, since ‘863 already claims the oral form, the peptides, inclusion of a coated acid, and a tablet formulation, and the skilled artisan has a limited number of acid salts of amino acids that includes Arg-HCl. There would have been a reasonable expectation of success because ‘863 already sets forth the tablet, peptide, and coated acid, and the skilled artisan merely has to select from a limited list of known acid salts of amino acids to reach the claimed oral-gastric formulation. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claim 33, coating of the acid particles, in this case Arg-HCl, constitutes a separation layer from the active peptide of 1-6 kDa being calcitonin, PTH, PTH truncates, and amidated PTH truncates.
With respect to claims 34-36, as noted above the ‘863 art suggests PTH and PTH fragments. The ‘863 art also suggests that GLP-1s can be part of a formulation, i.e. a GLP-1 agonist (see e.g. Col.9 lines 7-13).
Response to Arguments:
The Applicants summarize the rejection of record.
The Examiner finds no issues with the summary as provided.
The Applicants summarize the ‘863 art.
The Examiner argues as found in the rejection of record that ‘863 provides for acid particles in combination with an active peptide, which reasonably leads to a combination of at least PTH with Arg-HCl.
The Applicants argue claims 32 and 33 relate to pharmaceutical compositions lack an enteric coating. The Applicants argue these compositions would be adsorbed prior to intestinal arrival and that ‘863 is not directed to intestinal delivery. The Applicants argue one of ordinary skill in the art would not modify the ‘863 composition to allow particular efficient delivery of peptides via transmucosal routes. The Applicants argue a different purpose for ‘863 and would not be a relevant starting point for the claimed invention.
The Examiner agrees that the compositions as claimed lack an enteric coating, as does ‘863. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., intestinal delivery of the peptide and transmucosal delivery) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In this case, one of ordinary skill would utilize ‘863 since nothing in the claims explicitly requires transmucosal delivery or adsorption in the intestines.
The Applicants argue the present application is directed to a different approach to stabilize peptides through pH adjustment to reduce activity of proteolytic enzymes. The Applicants argue this is distinct from ‘863 and reinforces that one of ordinary skill in the art would not have arrived at the claimed subject matter from ‘863.
The Examiner again argues that the Applicants’ are arguing features which are not claimed. Nothing in claims 32 or 33 requires any change in pH of the composition to a specific level or that proteolytic enzyme activity be reduced. The claims as written are such that ‘863 does not constitute a materially different composition or a teaching away from the claimed invention. In response to applicant's argument that the instant application utilizes a different approach to stabilize peptides though pH adjustment and reduction of proteolytic activity, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The Applicants argue ‘863 does not provide a finite number of predictable solutions. The Applicants argue ‘863 generally refers to pH-lowering agents and broadly recites such compounds as suitable. The Applicants argue ‘863 refers to compounds such as aluminum chloride, zinc chloride, salts of amino acids, carboxylic acid, or phosphate esters. The Applicants argue the possible combinations was not finite or easily predictable such that the claimed invention could be reached via routine optimization. The Applicants argue the only composition in ‘863 is citric acid that is distinct from the claimed formulations.
The Examiner disagrees. As noted in the rejection of record, claim 10 states options being citric acid, tartaric acid, and salts of amino acids. While salts of amino acids could be considered broad, as also indicated the ‘863 art specifically highlights hydrochloride salts of amino acids, including naturally occurring amino acids and totaling 31 amino acids. The list is therefore both finite and readily optimizable given the ‘863 guidance. The Examiner does not dispute that the Examples of ‘863 utilize citric acid, but this argument ignores the other suggestions in ‘863 that amino acid salts can be the acid particle for the formulation, including Arg-HCl.
The Applicants argue a lack of reasonable expectation of success given the experimental data of ‘863 only exemplifying citric acid.
The Examiner disagrees. As argued above, the guidance from ‘863 indicates that amino acid salts can be utilized. ‘863 offers a finite number of amino acids as suggested for utilization, and specifically highlights a hydrochloride salt. Thus, even if citric acid is utilized in examples the other guidance of ‘863 offers the skilled artisan an expectation that an amino acid salt, including Arg-HCl, would be useful in their formulation as the acid particle.
The Applicants argue nonobviousness.
The Examiner disagrees for the reasons found above.
The Applicants argue hindsight reasoning.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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). The ‘863 art suggests using acid particles in combination with a therapeutic peptide. The guidance of ‘863 is further that acid salts of amino acids are useful. The list of amino acids for such choice is highly limited. The hydrochloride salts are specifically discussed. Thus, one of ordinary skill in the art is only utilizing the knowledge and guidance from ‘863 rather than relying on knowledge only found in the Applicants’ disclosure.
The Applicants’ arguments have been considered but are not persuasive. The rejection is modified and maintained.
Allowable Subject Matter
Claims 38 and 39 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The prior art does not recognize pharmaceutical compositions of octreotide with an excipient selected from arginine free base, EDTA tetrasodium salt, trisodium phosphate, tris(hydroxymethdyl)aminomethande, lysine, and calcium hydroxide, where the composition is formulated for transmucosal delivery. Similarly, the art does not recognize a pharmaceutical composition of octreotide with arginine free base or arginine HCl formulated for oral-gastric administration in tablet form and lacking an enteric coating or two or more peptide drugs contained therein. The closest prior art, Maggio E and Grasso P discloses oral administration of octreotide in combination with Intravail® and EDTA (see e.g. Regulatory Peptides 167:233-238, published 11 April 2011). Maggio and Grasso do not disclose that the EDTA is EDTA tetrasodium salt. The Maggio and Grasso art provides for transmucosal delivery, but fails to disclose or suggest the excipients as found in claim 1. Similarly, Maggio and Grasso fail to disclose or suggest an oral-gastric tablet form as in claim 32 utilizing arginine free base or arginine HCl. Accordingly, the claimed compositions of claims 38 and 39 are novel and unobvious pending consideration of any amendments Applicants may make in response to this action.
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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/Z.J.M/Patent Examiner, Art Unit 1658 /SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658