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 .
DETAILED ACTION
Claim Status
Claims 1-2, 6, 10-12, 14-16, 25-30, 35-36, 38-41, 43, 47, 51, 55-61 and 65 are pending. Claim 6 has been amended. Claims 1-2, 6, 10-12, 14-16, 25-30, 36, 38-41, 43, 55-56, 59-61 and 65 are being examined in this application. In response to the restriction requirement, Applicants elected Group I, insulin aspart, citrate, EDTA and dodecyl maltoside. Claims 35, 47, 51 and 57-58 are withdrawn as being drawn to a nonelected species/invention.
Response to Amendment
The declaration under 37 CFR 1.132 filed on 9/16/2026 is insufficient to overcome the rejection of claims 1-2, 6, 10-12, 14-16, 25-30, 36, 38-41, 43, 55-56, 59-61 and 65 based upon 35 USC § 103 as set forth in the last Office action because:
Applicant argues that “[W]ilson and Joseph begin from opposite formulation strategies. Wilson is expressly directed to hexameric "stabilized ultra-rapid-acting insulin formulations" (see, e.g., Wilson, page 29, line 33 to page 30, line 3) that rely on defined zinc-to-insulin ratios specifically, maintaining a zinc-to-insulin hexamer ratio between> 0.3 and 2.6, and "most preferably, between 0.5 and 0.9", to favor hexamer formation (see, e.g., Wilson, page 3, lines 26-31; and page 7, lines 20-24). Wilson uses that zinc-dependent hexameric structure to preserve insulin stability "in the bottle" and thereby achieve commercial shelf-life stability (see, e.g., Wilson, page 34, lines 5-11). Specifically, Wilson's formulations rely on zinc-stabilized hexamers at concentrations that maintain the hexameric state required for regulatory shelf-life stability. Joseph teaches the contrary approach. Joseph is directed to "substantially zinc-free" fast-acting formulations containing modified, monomeric or dimeric insulin analogues that Joseph defines to be an insulin that is stable for at least 30 days at 25° C. when it is formulated substantially without zinc (e.g., less than about 0.05 moles of zinc per mole of insulin) and thus present in solution predominately in the monomeric or dimeric form as opposed to the zinc-hexameric form. Joseph, paragraph [0048], emphases added, see also paragraph [0011]. Joseph emphasizes that conventional zinc-insulin hexamers are undesirable for rapid absorption and action because they must disassemble after injection before insulin can enter systemic circulation (Joseph, paragraph [0006]). Joseph's formulations therefore deliberately exclude zinc to discourage hexamer assembly (see, e.g., Joseph, paragraph [0011])”.
Applicant also argues that “[T]he formulation strategies of Wilson and Joseph are not complementary; they are contradictory. The scientific literature recognizes that native human insulin and standard rapid-acting analogues such as insulin aspart can self-associate into stable zinc coordinated hexamers at physiological pH in the presence of zinc, whereas zinc removal promotes dissociation into monomers and dimers that are more susceptible to denaturation, amyloid fibril formation, and physical precipitation (see, e.g., Brange et al., J. Pharm. Sci., 86:517-525 (1997); Dunn, Biometals, 18:295-303 (2005); and Joseph, paragraph [0006]). A person of ordinary skill in the art seeking to preserve Wilson's zinc stabilized hexameric insulin/rapid-acting insulin structure would not have looked to Joseph's instruction to remove zinc. Applying Joseph's "substantially zinc-free" requirement to Wilson would undermine the very hexameric stabilization mechanism on which Wilson depends and would render Wilson's formulation unsuitable for its intended shelf-life purpose. Incorporating Joseph's zinc-free mandate into Wilson's zinc-dependent hexameric insulin/rapid-acting insulin formulation destroys Wilson's primary stabilization strategy”.
Applicant further argues that “[N]either Wilson, nor Joseph meaningfully point a person skilled in the art to an alkyl glycoside such as DDM. Wilson, the primary reference in the Patent Office's rejection, simply mentions that its compositions may contain "wetting agents such as polysorbates, glycerin and poloxamers, non-ionic and ionic surfactants, food acids and bases (e.g. sodium bicarbonate), and alcohols, and buffer salts for pH control" (Wilson, page 14, lines 18-23). Moreover, none of the working compositions exemplified in Wilson contain a surfactant. Furthermore, on May 5, 2017, as today, surfactants such as nonionic surfactants, were known to not be generically interchangeable in complex biological solutions such as the formulations claimed in the '826 Application. Different non-ionic and ionic surfactants can interact with insulin in non-linear and system-dependent ways. Joseph, in paragraph [0075] lists broad open-ended categories of possible stabilizing agents, including non-ionic and ionic surfactants, bile salts, fatty-acid esters, amino acids, non-reducing carbohydrates, and organic ketones. This non-limiting "exemplary" list contains dozens of disparate chemical classes, none of which are presented as interchangeable or individually preferred. Moreover, Joseph does not exemplify any working formulation containing DD~1I or any other surfactant (Joseph, Examples 1-5, paragraphs [0 157]-[0176]), and it expresses no preference for an alkyl glycoside over the many other listed exemplary stabilizing agents. From the perspective of a person of ordinary skill in the art, Joseph provides no technical preference, specific guidance, or working examples pointing to an alkyl glycoside such as DDM among its open-ended list of compounds. Nothing in Joseph's disclosure provides a person of ordinary skill in the art with a technical reason or motivation to select DDM over any of the other listed options. Likewise, neither Wilson nor Joseph teaches that a surfactant is necessary to obtain a stable insulin formulation with a rapid-acting time-action profile. Hovgaard does not supply the missing motivation for a person of ordinary skill in the art considering Wilson alone or Wilson in view of Joseph to modify the formulations or teaching of Wilson to arrive at the formulations claimed in the '826 Application. Hovgaard evaluated alkyl maltosides including DDM in a simple 0.1 M phosphate buffered saline solution at pH 8.0 using native bovine insulin (Hovgaard, page 108, section 2.2). That lest system did not contain citrate. By contrast, Wilson (page 3, lines 19-21, page 12, lines 3-8; and claim 6) and the elected species of the pending claims require citrate at defined concentrations. The absence of citrate in Hovgaard is significant because citrate changes the zinc-binding environment, and the zinc-binding environment is central to Wilson, Joseph, and claimed formulation strategy. Citrate is not an inert background ingredient. In protein physical chemistry, citrate acts as a competitive zinc-binding agent that sequesters stabilizing ionic zinc from the insulin hexamer and thereby affects the stability of the protein matrix (see, e.g., Pohl et al., J. Diabetes Sci. TcchnoL, 6(4):755---763 (2012); and Dunn, Biomelals, 18:295-303 (2005)). Nor does the activity of a surfactant in a simple formulation necessarily translate to the same activity in complex biological solutions. The same surfactant can interact with insulin in different formulations in non-linear and system-dependent ways, depending on ionic strength, zinc availability, insulin self-association state, pH, and co-excipient composition (see, e.g., Zbacnik et al, J. Pharn1. Sci., 106(3):713-733 (2017), Sluzky et al., Proc. Natl. Acad. Sci. USA, 88:9377-9381 (1991); Hovgaard; and Pohl et al., J. Diabetes Sci, Technol., 6(4):755-763 (2012)). Because citrate is a known destabilizer of insulin hexamers, a person of ordinary skill in the art evaluating Hovgaard's results in a simple, citrate-free phosphate buffer would have had no reasonable expectation that DDM would retain its stabilizing effect in Wilson's complex, citrate containing, zinc dependent formulation. Nothing in the prior art provides a technical basis to expect that DDM would have a stabilizing activity in such a fundamentally different chemical environment; assuming it would do so is unsupported speculation”.
Applicant additionally argues that “[N]one of the cited references identifies the claimed concentration boundaries as predictable result-effective variables. To the contrary, the relevant chemistry would have taught a person of ordinary skill in the art that surfactant identity and concentration, zinc availability, citrate concentration, EDTA level, ionic strength, and insulin analogue selection are interdependent. An unsuitable surfactant or an unfavorable component ratio can remove protective zinc, change local protein-surface interactions, and promote aggregation or fibrillation pathways (sec, c,g., Dunn, Biometals, 18:295-303 (2005); Ciszak & Smith, Biochemistry, 33: 1512-1517 (1994); Brange et al., J, Pharm. Sci., 86:517---525 (1997); Nielsen et al., Biochemistry, 40:6036---6046 (200 l); Pohl et al., J. Diabetes Sci. Technol., 6(4):755---763 (2012); Krasner et aL, J. Diabetes Sci. Technol., 6(4):786-796 (2012); Zbacnik et al., J. Pharm. Sci., 106(3):713-733 (20 I 7); Zapadka et al., Interface Focus, 7:20170030 (2017))). Arriving at the claimed formulation therefore would have required re-designing and re-optimizing the entire multi-component matrix, not merely performing routine linear optimization of one or more components”.
Applicant’s arguments are not persuasive.
In response to Applicant's piecemeal analysis of the references, it has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981).
In the instant case, Wilson et al. clearly teach a liquid formulation comprising insulin aspart, zinc ions, citrate, EDTA and non-ionic surfactants.
Thus, it would have been obvious to use any known non-ionic surfactant (see MPEP 2144.06), regardless of whether the formulation is with or without zinc.
On the other hand, Joseph et al. teach liquid pharmaceutical compositions comprising an effective amount of insulin aspart, zinc, EDTA, citrate, and a surfactant such as dodecyl-3-D-maltoside; and Hovgaard et al. teach that dodecyl-3-D-maltoside stabilizes insulin.
Hovgaard et al. further teach that increasing concentrations of dodecylmaltoside resulted in higher insulin stabilization.
Therefore, one of ordinary skill in the art concerned with insulin stability would have reasonably expected to stabilize insulin in the invention of Wilson et al. by using the non-ionic surfactant of Joseph et al. and Hovgaard et al. (i.e. dodecyl-3-D-maltoside).
Furthermore, Applicant did not provide any evidence showing that the inclusion of dodecyl-3-D-maltoside in the formulation of Wilson et al. would have been expected to change the effectiveness of said formulation.
With respect to Applicant’s arguments regarding nonionic surfactants not being interchangeable in complex biological solutions, it is noted that not a single reference was provided to back this statement.
Moreover, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham, including the exemplary rationales: (A) Combining prior art elements according to known methods to yield predictable results;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(B) Simple substitution of one known element for another to obtain predictable results;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP 2143).
In the instant case, (A)-(B) and (E)-(G) above are satisfied.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
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.
This rejection is maintained.
Claims 1-2, 6, 10-12, 14-16, 25-30, 36, 38-41, 43, 55-56, 59-61 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (WO 2015/120457) in view of Joseph et al. (US 2016/0375104) and Hovgaard et al. (International Journal of Pharmaceutics 132 (1996) 107-113).
With respect to claims 1, 10-11, 14, 28-29 and 36, Wilson et al. teach an injectable (i.e. liquid) formulation comprising insulin, zinc ions, citrate, EDTA and non-ionic surfactants (claims 1, 5-6; page 5, lines 29-30; page 14, lines 18-21), wherein the insulin is an insulin analog (claim 3), and wherein the insulin analog is insulin aspart (page 5, lines 24-25).
Wilson et al. further teach that the concentration of citrate is between 0.6 mg/ml and 2.4 mg/ml (claim 9; Example 4). The molecular weight of citrate is 189.1 g/mol, therefore the concentration of citrate is between 3.17mM (0.6/189.1*100) and 12.6mM (2.4/189.1*100).
Wilson et al. also teach 100 IU of the insulin analog and 0.0197 mg zinc ion and (page 18, lines 10-13), wherein 100 U/ml corresponds to 3.86 mg (page 19, lines 21-23). Thus, the concentration of zinc ion is 0.51% (0.0197*100/3.86).
Wilson et al. do not teach the non-ionic surfactant is an alkyl glycoside.
Joseph et al. teach pharmaceutical compositions comprising an effective amount of a monomeric insulin analogue or dimeric insulin analogue and an effective amount of one or more charge masking agents (claim 2), wherein the composition is an aqueous formulation (claim 3), wherein the composition comprises zinc (claim 5), wherein the charge-masking agent is EDTA (claim 7), wherein the composition comprises citrate at a concentration of 1-25 mM (paras [0064], [0074], [0175]-[0176]; Table 1), wherein the insulin is insulin aspart (paras [0050]-[0051]), wherein the insulin is present at a concentration of 100 U/ml (para [0048]), wherein the composition comprises a surfactant (claim 40), and wherein the surfactant is dodecyl-3-D-maltoside (i.e. an alkyl glycoside) (para [0075]).
Joseph et al. also teach that the composition comprises one or more agents that maintain or adjust the isotonicity, such as sodium chloride (para [0073]), phenol and m-cresol (claim 40; Table 1; para [0081]), nicotinamide, nicotinic acid and/or magnesium salts (claim 7; paras [0077], [0079], [0084], [0086]).
Hovgaard et al. teach that dodecyl-3-D-maltoside stabilizes insulin (abstract; passim), and further teach that “[A]s the concentrations of dodecylmaltoside were raised, higher stabilization was observed (page 112, left column, 1st para).
It would have been obvious, with a reasonable expectation of success, to one of ordinary skill in the art to use the non-ionic surfactant of Joseph et al. (i.e. dodecyl-3-D-maltoside), because Joseph et al., just like Wilson et al. is drawn to insulin formulations comprising insulin, zinc ions, citrate, EDTA and a non-ionic surfactant, and further because Hovgaard et al. teach that dodecyl-3-D-maltoside stabilizes insulin.
One of ordinary skill in the art concerned with insulin stability (taught by Wilson et al. and Joseph et al.) would have reasonably expected dodecyl-3-D-maltoside to stabilize insulin as taught by Hovgaard et al.
With respect to claim 2, Wilson et al. teach the insulin is insulin aspart (Example 12, Figures 5A, 7, 8A).
With respect to claims 6 and 59, Wilson et al. teach the insulin is present at a concentration of 100, 200, 400 or 500 IU/ml (claim 4; page 3, lines 16-18; page 9, lines 2-4).
With respect to claims 12, 60 and 65, Wilson et al. teach the concentration of citrate is between 0.6 mg/ml and 2.4 mg/ml (claim 9; Example 4). The molecular weight of citrate is 189.1 g/mol, therefore the concentration of citrate is between 3.17mM (0.6/189.1*100) and 12.6mM (2.4/189.1*100). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection (MPEP § 2144.05).
With respect to claims 26-27, Wilson et al. teach the concentration of EDTA is less than 0.2 mg/mL (page 12, lines 28-29). The molecular weight of EDTA is 292.24 g/mol, therefore the concentration of EDTA is less than 0.68 mM. A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection (MPEP § 2144.05).
With respect to claim 30, Wilson et al. teach that the concentration of zinc ion is between 0.413 mM to 0.504 mM (page 21, lines 23-24). Thus, the molar ratio of ionic zinc to EDTA is >0.74:1, which overlaps with the instantly claimed range.
With respect to claim 38, Wilson et al. teach the final formulation can include additional excipients commonly found in the commercial preparations of insulin and insulin analogs, including sodium chloride (page 15, lines 2 and 31), and further teach the insulin is present at a concentration of 100, 200, 400 or 500 IU/ml (claim 4; page 3, lines 16-18; page 9, lines 2-4).
With respect to claim 38, Wilson et al. teach the formulations comprise 50mM or 100 mM nicotinamide (claim 11; page 24, line 17; Tables 6-8).
With respect to claim 39, Wilson et al. teach the formulation comprises isotonic agents such as sodium chloride (page 15, lines 2 and 31). Thus, the formulation is believed to be substantially isotonic.
With respect to claim 40, Wilson et al. teach the pH is 7 (claim 16).
With respect to claim 41, Wilson et al. teach the formulation further comprises m-cresol (claim 18).
With respect to claim 43, Wilson et al. teach the formulation further comprises nicotinamide (claim 11) and/or magnesium salts (claim 12).
Wilson et al. do not teach the claimed concentration of the zinc binding species claimed in (iv) (e.g. EDTA).
Wilson et al. also do not teach the limitations of instant claims 25, 55-56 and 61.
However, as discussed above, Wilson et al. teach the composition comprises a non-ionic surfactant, citrate, and zinc, but do not teach the concentration of said non-ionic surfactant (claims 25 and 61) and citrate (claim 55), nor the ratio of zinc to citrate (claim 56).
The MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)”.
Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum concentration of the surfactant and zinc, and the ratio of zinc to citrate by normal optimization procedures known in the pharmaceutical art.
Response to Arguments
Applicant’s arguments have been addressed above under Response to Amendment on pages 2-9.
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 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.
This rejection is maintained.
Claims 1-2, 6, 10-12, 14-16, 25, 28, 36, 38-41, 43, 55-56, 59, 61 and 65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6-25 and 27-32 of copending Application No. 15/978329 in view of Joseph et al. (US 2016/0375104).
With respect to claims 1, 6, 10-12, 14, 28, 40, 55, 59 and 65, ‘329 teaches a pharmaceutical composition comprising: a. an insulin, in a concentration from about 100 to about 200 U/mL; b. citrate, in a concentration from about 15 to about 35 mM; c. zinc, in a concentration from about 0.3 to about 1.1 mM; and d. a preservative; and wherein the zinc concentration is sufficient to provide at least enough zinc ions for the insulin to form hexamers; and wherein the pH of the composition is from about 7.0 to 7.8; and wherein the composition does not include EDTA (claim 1). ‘329 also teaches that the composition comprises a surfactant (claims 13, 23 and 31), wherein the concentration of the surfactant ranges from about 0.001 to about 2% w/v (page 4, line 9 of the specification). ‘329 further teaches the composition does not include EDTA, EGTA, alginic acid, alpha lipoic acid, DMSA or CDTA (page 26, lines 16-19 of the specification). Please note that it is proper to turn to and rely on the disclosure of a patent application to ascertain what constitutes an obvious modification. This position is supported by the courts. See In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
Thus, in some embodiments, the formulation comprises EGTA.
‘329 does not teach the surfactant is an alkyl glycoside.
The teachings of Joseph et al. have been discussed above.
It would have been obvious, with a reasonable expectation of success, to one of ordinary skill in the art to use the surfactant of Joseph et al. (i.e. dodecyl-3-D-maltoside), because Joseph et al., just like ‘329 is drawn to insulin formulations comprising insulin, zinc, citrate, and a surfactant.
With respect to claim 2, ‘329 teaches the insulin is insulin lispro (claim 2).
With respect to claims 25 and 61, ‘329 teaches the composition comprises a surfactant in a concentration from about 0.001 to about 0.2 % w/v (claim 31). Thus, the composition comprises 100 to 2000 mg per 1 mL.
With respect to claim 36, ‘329 teaches the insulin is insulin aspart (page 7, lines 25-28).
With respect to claim 38, ‘329 teaches the composition comprises sodium chloride (claims 10-12 and 23).
With respect to claim 39, ‘329 teaches the composition is isotonic (para bridging pages 20-21).
With respect to claim 41, ‘329 teaches the preservative is selected from the group consisting of phenol and metacresol and mixtures thereof (claim 17).
With respect to claim 43, ‘329 teaches the composition further comprises magnesium chloride (claims 6-7 and 20-23).
‘329 does not teach the claimed concentration of the zinc binding species claimed in (iv) (e.g. EGTA).
‘329 also does not teach the limitation of instant claim 56.
However, as discussed above, ‘329 teaches the composition comprises a surfactant, citrate, and zinc, but do not teach the concentration of said surfactant, nor the ratio of zinc to citrate.
The MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)”.
Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum concentration of the surfactant and the ratio of zinc to citrate by normal optimization procedures known in the pharmaceutical art.
Response to Arguments
Applicant requested the rejection be held in abeyance until otherwise allowable subject matter is identified.
This rejection is maintained.
Claims 1, 2, 6, 10-12, 15-16, 25-30, 39-41, 43, 55-56, 59-61 and 65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11278624 in view of Joseph et al. (US 2016/0375104).
With respect to claims 1, 6, 10-12, 55, 59-60 and 65, ‘624 teaches an aqueous liquid pharmaceutical formulation comprising an insulin analogue at a concentration of 100-1000 U/ml, ionic zinc at a concentration of 0.25-1% by weight of zinc based on the weight of the insulin analogue in the formulation, citrate as a chelating agent at a concentration of 10-50 mM and polysorbate 80 at a concentration of 0.05-0.5 mg/ml (claim 1).
‘624 does not teach the formulation comprises EDTA and alkyl glycoside.
The teachings of Joseph et al. have been discussed above.
The MPEP 2144.06 states that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As the court explained in Crockett, the idea of combining them flows logically from their having been individually taught in prior art.
Furthermore, the MPEP 2144.06 states that it is obvious to substitute equivalents known for the same purpose.
It would have been obvious, with a reasonable expectation of success, to one of ordinary skill in the art to add the surfactant (i.e. dodecyl-3-D-maltoside) and the chelating agent (i.e. EDTA) of joseph et al., because Joseph et al., just like ‘624 is drawn to insulin formulations comprising insulin, zinc, citrate, and a surfactant.
With respect to claim 2, ‘624 teaches the insulin is insulin aspart (claim 3).
With respect to claims 25 and 61, ‘624 teaches the surfactant (i.e. polysorbate 80) in a concentration of 0.05-0.5 mg/ml (i.e. 50-500 g/ml). Thus, it would have been obvious to either use 50-500 g/ml of dodecyl-3-D-maltoside, or to use 50-500 g/ml of total concentration of dodecyl-3-D-maltoside and polysorbate 80.
With respect to claims 26-29, ‘624 teaches that when the chelating agent is EDTA, the concentration is in the range 0.1-2mM (column 5, lines 23-27). Please note that it is proper to turn to and rely on the disclosure of a patent application to ascertain what constitutes an obvious modification. This position is supported by the courts. See In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
With respect to claim 30, ‘624 teach that the concentration of the ionic zinc in the formulation will (for example, for a formulation containing 100 U/ml of insulin or insulin analogue) typically be more than 0.015 mM (column 4, lines 46-49). Thus, the molar ratio of ionic zinc to EDTA is >0.15:1
With respect to claim 39, ‘624 teaches the composition is isotonic (claim 12).
With respect to claim 40, ‘624 teaches the pH is in the range 5.5 to 9.0 (claim 13).
With respect to claim 41, ‘624 teaches the formulation further comprises a preservative selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride and benzethonium chloride (claim 17).
With respect to claim 43, ‘624 teaches that “[t]he formulations of the invention may optionally comprise nicotinamide. The presence of nicotinamide may further increase the speed of onset of action of insulin formulated in compositions of the invention (column 8, lines 10-13).
With respect to claim 56, ‘624 teach that the concentration of the ionic zinc in the formulation will (for example, for a formulation containing 100 U/ml of insulin or insulin analogue) typically be more than 0.015 mM (column 4, lines 46-49), and the concentration of citrate is 10-50 mM (claim 1). Thus, the molar ratio of ionic zinc to citrate is >0.0045:3.
Response to Arguments
Applicant requested the rejection be held in abeyance until otherwise allowable subject matter is identified.
Conclusion
THIS ACTION IS MADE FINAL. 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 SERGIO COFFA whose telephone number is (571)270-3022. The examiner can normally be reached M-F: 6AM-4PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MELISSA FISHER can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SERGIO COFFA Ph.D./
Primary Examiner
Art Unit 1658
/SERGIO COFFA/Primary Examiner, Art Unit 1658
Prosecution Insights