Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
America Invents Act
The present application is being examined under the pre-AIA first to invent provisions. 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.
DETAILED ACTION
Applicant’s response (amendments, arguments, IDS’s (3)) filed with or following the RCE is acknowledged.
Claims 1-3,5-9,11-14,17-23 and 29-33 (claim 33 new), following the amendments, are pending and examined on the merits. The rejections previously of record (obviousness and double patenting) have been modifications necessitated by amendment. A new rejection necessitated by amendment is applied under 35 USC 112 1st paragraph (pre-AIA ; new matter/possession under written description).
Applicant-Initiated Interview Summary (5/8/26, Attached): A productive post-RCE interview was held with applicant’s representative (AR) to go over the newly amended claim scope to long-acting (rather than fast-acting) insulins, such as that named insulin icodec. As discussed by interview, the latter has raised new issues under 35 USC 112 1st Paragraph (pre-AIA ) (written description/possession) which are set forth below. Note: Notwithstanding that the new product claim scope was not by original presentation, the examiner is willing to search and examine such to advance prosecution on the merits for applicant.
Prior to these amendments, the claim scope here had mirrored that of abandoned parents, including claim dependency edits and/or cancellation of claims: U.S. Patent Application Nos. 17/864,645 and 17002063 – both abandoned after the first Office action final sent in each (as here). As such the claim rejections - and indication of allowable subject matter scope. The earliest direct chain application was allowed: U.S. Patent No. 9,839,675. (See also later family U.S. Patent Nos. 9,839,692; 9,895,424; and 10,610,595 – drawn to similar but distinct formulations.).
Potentially Allowable Subject Matter – Similar to that in Issued Parents Patents –
If New 35 USC 112 1st Paragraph (pre-AIA ) Written Description
New Matter/Possession Issues be Traversed (Re: Icodec)
Claim 18 and new claim 33 may be allowable if applicant can find/argue sufficient support – including identification of the earliest effective filing date support thereof - for insulin icodec (see 35 USC 112 1st Paragraph (pre-AIA ) Written Description (Possession) rejection below) and if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The prior art was not found to reasonably teach or suggest the claimed pharmaceutical formulation of claims 18 and 33 comprising the specific 8-9 elements - at the specific amounts.
RELEVANT STATUTORY AND/OR CASE-LAW BASED REJECTIONS
Claim Rejections - 35 USC § 103 – Obviousness, Modified, Necessitated by Amendment
Claims 1-3, 6-9, 11-13, 19-23 and 29-32 (but not 5, 14, 17-18, and 33 drawn to insulin icodec as no prior art was found thereon prior to the earliest effective filing date – but see 35 USC 112 1st Paragraph (pre-AIA ) New Matter/Written Description Rejection below) are rejected under 35 U.S.C. 103(a) as obvious over Schlichtkrull (US Patent No. 3091573, Novo Terapeutisk Lab AS, Denmark) in view of Norup et al. (US Patent No. 5866538, “Norup”), and further in view of Robinson et al. (US Pub. No. 2012/0225811, “Robinson”) and Pedersen et al. (US Pub. No. 2007/0010424, “Pedersen”) – the latter reference Pederen (see para’s 43, 59 (& especially section title thereof), 62, and 346-347) of which teach the instant newly amended claim scope to “non-natural, long-acting analogue” and/or derivative of insulin” (but not the species icodec as in instant claims 5, 14, 17-18, and 33) – as interchangeable with the formerly claimed rapid/fast/basal insulins:
[0043] FIG. 2B is a schematic diagram showing the A-chain and the B-chain of human insulin and the disulfide bridges present in human insulin compared to long acting insulin analogues, glargine (SEQ ID NO: 91) and detemir (SEQ ID NO: 93).
Rapid and Long Acting Insulins
[0059] The dicarba analogues of insulin of the present invention may be rapid or long acting insulins. The activity of the insulin may be modulated by mutating the native amino sequence to disrupt the self association between monomers of insulin, or by modification of one or more amino acids of the native insulin sequence. The activity of the insulin may be modulated by mutating the native amino sequence or by modification of one or more amino acids of the native insulin sequence to disrupt the solubility of the insulin. These modifications are encompassed by the dicarba analogues of insulin of the present invention.
[0062] In direct contrast, intermediate- and long-acting insulin preparations display slower onsets of action and can often last up to 24 hours. Initial preparations involved altering the solubility profile of native insulin via complexation with zinc, or using additives such as protamine or phenol-like derivatives. This produced the original isophane insulin suspensions (NPH), Humulin N/L and Novolin N/L, which are absorbed slowly from the subcutaneous injection site. Unfortunately, use of these intermediate-acting insulin suspensions produces highly variable results, leading to inconsistent onset and duration of effect. More recently, however, sequence modification has been used to extend the duration of insulin action in a safe and reproducible manner. Two analogues, insulin glargine and detemir, are now available for commercial application (FIG. 2B). Insulin glargine exploits the reduced solubility of insulin at physiological pH to control release. Addition of two arginine residues to the C-terminus of the B-chain, in addition to a glycine substitution at A21, increases the isoelectric point of the native molecule and increases formulation stability of the peptide in acidic media. These structural alterations generate an analogue that precipitates in the presence of zinc at the site of subcutaneous injection, and then slowly and reproducibly solubilises to produce a steady supply of insulin at target tissues. Insulin detemir on the other hand, exerts its activity through the presence of a long fatty acid chain joined to the c-amino group of Lys.sub.B29. This allows reversible, non-covalent binding to albumin in serum, which produces a human insulin analogue that displays a flatter and significantly longer time-action profile when compared to the native molecule. Although many diabetic patients are now enjoying the convenience of these long-acting analogues, there is still a considerable desire to improve basal insulin treatments. Unfortunately, both insulin variants have significant draw-backs, with glargine showing enhanced IGF-I receptor binding affinity, and detemir possessing reduced in vivo potency. In addition, both these analogues fail to produce a 24 hour duration of action, and hyperglycemia is still a common occurrence with these basal treatments. These modifications to the native insulin sequence, and the corresponding dicarba analogues of insulin are encompassed by the present invention.
[0346] Presently, different forms of typically subcutaneously-administered insulin preparations have been developed to provide different lengths of activity (activity profiles), often due to ingredients administered with insulin, ranging from short or rapid activity (e.g., solutions of regular, crystalline zinc insulin for injection; semilente insulin (prompt insulin zinc suspension); intermediate activity (e.g., NPH (isophane insulin suspension; lente (insulin zinc suspension; lente is a mixture of crystallized (ultralente) and amorphous (semilente) insulins in an acetate buffer); and slow activity (ultralente, which is extended insulin zinc suspension; protamine zinc). Short-acting insulin preparations that are commercially available in the U.S. include regular insulin and rapid-acting insulins. Regular insulin has an onset of action of 30-60 minutes, peak time of effect of 1.5 to 2 hours, and a duration of activity of 5 to 12 hours. Rapid acting insulins, such as aspart (Humalog.RTM.)/lispro (Novolog.RTM.), have an onset of action of 10-30 minutes, peak time of effect of 30-60 minutes, and a duration of activity of 3 to 5 hours. Intermediate-acting insulins, such as NPH (neutral protamine Hagedorn) and Lente insulins (insulin zinc suspension), have an onset of action of 1-2 hours, peak time of effect of 4 to 8 hours, and a duration of activity of 10 to 20 hours. In the case of long-acting insulins, Ultralente insulin has an onset of action of 2-4 hrs, peak time of effect of 8-20 hours, and a duration of activity of 16 to 24 hours, while Glargine insulin has an onset of action of 1 to 2 hours, a duration of action of 24 hours but no peak effect. There are over 180 individual insulin preparations available world-wide. Approximately 25% of these are soluble insulin (unmodified form); about 35% are basal insulins (mixed with NPH or Lente insulins, increased pl, or isoelectric point (insulin glargine), or acylation (insulin detemir); these forms have reduced solubility, slow subcutaneous absorption and long duration of action relative to soluble insulins); about 2% are rapid-acting insulins (e.g., which are engineered by amino-acid change, and have reduced self-association and increased subcutaneous absorption); and about 38% pre-mixed insulins (e.g., NPH/soluble/rapid-acting insulins; these preparations have the benefit, e.g., of reduced number of daily injections). In many cases, regimens that use insulin in the management of diabetes combine long-acting and short-acting insulin. It is contemplated that the dicarba insulin analogues of the present invention, and in particular the oral formulations which include the dicarba insulin analogues preferably together with a pharmaceutically acceptable delivery agent that facilitates absorption of the dicarba insulin analogue from the gastrointestinal tract, may be utilized in combination therapy to include an insulin that has rapid action, intermediate action, and/or slow action, as described above, in order to provide effective basal insulin levels in the, for example, diabetic patient. It will be appreciated that the combination therapy may comprise one or more dicarba insulin and one or more non-dicarba insulin such as for example any one of the commercially available insulins disclosed above. The rate of action of the insulin may be caused by virtue of its solubility, and/or by virtue of its half-life, etc. Thus, in alternative embodiments, the oral formulations of the present invention may be designed to provide the intermediate activity which is found with, e.g., a subcutaneously administered NPH insulin, or a slow action which is found with protamine zinc insulin. In each case, the oral formulations of the invention, which preferably include a pharmaceutically acceptable delivery agent which facilitates absorption of the insulin (as described herein) provide effective control of blood glucose levels, albeit for different time periods and with different plasma glucose time curves. Intermediate-acting and long-acting insulin may be prepared using methodologies known to those skilled in the art to provide a continuous level of insulin, similar to the slow, steady (basal) secretion of insulin provided by the normal pancreas. For example, Lantus.RTM., from Aventis Pharmaceuticals Inc., is a recombinant human insulin analog that is a long-acting, parenteral blood-glucose-lowering agent whose longer duration of action (up to 24 hours) is directly related to its slower rate of absorption. Lantus.RTM. is administered subcutaneously once a day, preferably at bedtime, and is said to provide a continuous level of insulin, similar to the slow, steady (basal) secretion of insulin provided by the normal pancreas. The activity of such a long-acting insulin results in a relatively constant concentration/time profile over 24 hours with no pronounced peak, thus allowing it to be administered once a day as a patient's basal insulin. Such long-acting insulin has a long-acting effect by virtue of its chemical composition, rather than by virtue of an addition to insulin when administered
[0347] In a preferred embodiment, administration of a pharmaceutical composition comprising a long-acting form of insulin (e.g. a therapeutic dicarba analogue of a long-acting form of insulin) is once or twice a day. In a preferred embodiment, administration of a therapeutic dicarba insulin providing short-acting insulin effect can be once, twice, three times, four times or more than four times daily, and can be at nighttime, in the morning and/or preprandially. In a more preferred embodiment, administration of the dosage form is preferably at nighttime or morning and three times preprandially, and more preferably is at nighttime and preprandially for breakfast, lunch and dinner. Preferably, the therapeutic dicarba insulin compositions are administered to such human patients on a chronic basis, e.g., for at least about 2 weeks. In certain preferred embodiments of the invention, the oral formulations of the invention provide two forms of insulin having different activity rates in order to simulate the biphasic release of insulin in non-diabetic humans. For example, such oral formulations may include a rapid-acting dicarba analogue (e.g. a therapeutic dicarba analogue of a rapid-acting insulin) together with a slow-acting dicarba analogue (e.g. a therapeutic dicarba analogue of a slow-acting insulin) so as to provide a first peak of insulin which occurs rapidly and is short-lived, followed by a second peak of insulin which occurs at a later time, but which preferably has a longer duration. In further alternatively preferred embodiments of the invention, the oral formulations of the invention include a rapid-acting dicarba analogue together with a secretagogue that promotes the secretion of insulin from the beta-cells at a time and to an extent which mimics the second phase release of insulin in non-diabetic humans.
Schlichtkrull expressly teaches insulin compositions comprising zinc (Zn) at a pH of 7 to 8, thus within a “pH value in the range of 6.0 to 9.0 and free of any additional buffering agent” as instantly claimed beyond the instantly recited buffering agents of insulin and optional protamine (col. 1, lines 54-72 to col. 2, lines 1-12). Schlichtkrull also includes the rationale as to why no additional buffering agents are needed as well as when additional buffering agents are needed when excess Zn (or other metals) are present in order to bind excess Zn/other metals (col. 2, lines 26-47). However, this is not the case as instantly claimed, as the Zn levels are low (instant claim 7) as in Schlichtkrull.
More specifically addressing each of the recited limitations of instant claim 1, Schlichtkrull teaches the following:
Insulin Analogue/Derivative: Schlichtkrull teaches the insulin may be an insulin derivative derived from the pig pancreas (col. 1, lines 54-56).
Zn(II) Ion (Note: Not Zn salt, such as acetate, a buffer): Schlichtkrull teaches that any Zn ion may be used in such preparations (col. 1, lines 54-65), which would naturally mean Zn(II) as immediately envisaged as a standard ion of Zn as instantly claimed (MPEP 2144.03 Official Notice taken that PHOSITA understands zinc ions as standard Zn(II) in zinc-insulin formulations; see by example Robinson as an evidentiary reference (para [0061]) teaching why the Zn(II) ion was used by PHOSITA with insulin aspart, namely insulin “aspart [is stored as a] stabilized Zn(II) hexamer” to “overcome inherent storage-stability issues”):
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A “pH value plainly within the range of 6.0 to 9.0 and free of any additional buffering
agent”: Schlichtkrull expressly teaches that the solution may “preemptively have a pH-value of 7-8, which would thus not require any additional buffering agent to achieve said neutral pH value in the range of 6.0 to 9.0 (col. 1, lines 70-72): “The process according to the invention is thus characteristic in that pig insulin is dissolved in an aqueous injectable medium having [or being given] a pH-value of 7-8.”
Free of any additional buffering agent; “Buffer-Free/Low Zn Level Balance” of
Schlichtkrull: Schlichtkrull teach that without buffers to bind excess Zn, Schlichtkrull requires that the zinc be at low levels (less than 1.7 mg per the percent of zinc) like that instantly claimed and covering the range instantly claimed in dependent claim 7 (0.0100-0.0600 mg/100 U insulin). For example, enough Zn as a “prerequisite to the crystallization of insulin” (Id.) and “which promote crystallization of the insulin . . . present in the solution in a concentration being just sufficiently high for the crystallization of the insulin” (col. 1, lines 59-61); but not so much as to “reduce the solubility of the insulin at neutral reaction”, e.g. pH 7-8, so “that no insulin precipitation will take place” (col. 2, lines 5-12). See Schlichtkrull, especially column 2, lines 26-47 (emphasis added by examiner):
The process according to the invention is therefore further characterized by the fact that, if use is made of an addition of a solution of a compound of one or more of the metals, such as zinc, cobalt, nickel and cadmium, which are prerequisite to the crystallization of insulin, or of insulin having a high content of these metals, in the absence of substances, such as buffering substances forming slightly soluble or complex compounds with the said metals, the solution is given a content of the metals of less than about 13 A 10 milliequivalent-s per litre, A indicating the number of international units of insulin per millilitre. With zinc as an example and an insulin concentration of 40 international units per millilitre, the produced solution should in the absence of e.g. phosphate and citrate buffers contain less than about 1.7 mg. percent of zinc. If, however, phosphate of citrate buffers are present, the produced preparation may contain considerably more zinc if only the amount of zinc ions being at the disposal of the insulin and consequently not bound by the buffering substance does not exceed the above mentioned upper limit.
The above was based on the discovery by Schlichtkrull that stable, neutral (pH 7-8) insulin compositions with metals such as Zn could be made without the addition of buffers being needed (col. 1, lines 54-72 to col. 2, lines 1-12; emphasis added by examiner):
The invention is based on the discovery that insulin produced from pig pancreas, in the following called pig insulin, has such a high solubility at a pH-value of 7 to 8 that no insulin precipitates will be formed at this pH-value so that it is ensured that, even when ions of such metals, preferably zinc, which promote crystallization of the insulin, are present in the solution in a concentration being just sufficiently high for the crystallization of the insulin, even after prolonged storage no precipitation of crystalline insulin will take place, which crystalline insulin in aqueous suspension containing ions of zinc or the like metals in a higher concentration is known to show a very highly prolonged insulin activity.
It is surprising that when employing pig insulin it is possible to produce stable insulin solutions having a pH- value of 7-8.
The process according to the invention is thus characteristic in that pig insulin is dissolved in an aqueous injectable medium having [or being given] a pH-value of 7-8.
As mentioned in the foregoing in the production of the acid insulin solutions known up to now use has sometimes been made of an addition of zinc chloride. It is known that zinc ions and ions of other crystallization-promoting metals, such as cobalt, nickel and cadmium, reduce the solubility of the insulin at neutral reaction. Hence, if in the process according to the invention use is made of an addition of a water-soluble zinc salt or a salt of one of the other crystallization-promoting metals, or if use is made of insulin having a high content of these metals, care should be taken that the produced insulin solution will be made to have such content of zinc ions or the like ions that no insulin precipitation will take place.
Regarding instant claim 1’s remaining required limitation of sodium chloride (NaCl):
While Schlichtkrull does teach that NaCl may be used in such formulations (Example 3), there is only one recitation of NaCl in Schlichtkrull (Example 3; NOTE: NaCl present in the exemplified formulation is the result of the neutralization of the aqueous HCl with the added 1N NaOH solution to adjust the pH to a value of 7.3 -7.5.). While Schlichtkrull teaches formulations “free of any additional buffering agent”, Example 3’s use of NaCl is a formulation that does include an “additional buffering agent” and the instant invention does not claim any additional buffers. Though long-used and art-recognized, Schlichtkrull does not provide a stated reason as to why PHOSITA uses NaCl in insulin formulations and thus a secondary reference is required to establish why PHOSITA would have equally used NaCl in the buffer-free insulin formulations of Schlichtkrull. This deficiency is cured by secondary reference Norup, discussed below.
Optional 6th Element of Instant Claim 1 - Protamine: With respect to the embodiment of instant independent claim 1, where protamine is present in the claimed formulations, it is noted that Schlichtkrull teaches formulations comprising both insulin and protamine (see col. 1, lines 20-26). Protamine being a fish protein long added to insulin preparations for its art-recognized use of delaying absorption of insulin.
Instant Claim 1 Gap: Thus, while Schlichtkrull teaches all the required elements of claim 1, including use of NaCl, Schlichtkrull did not per se teach why one of skill in the art would have equally have selected NaCl for use in buffer-free insulin formulation.
Secondary reference Norup teaches as titled “Insulin Preparations Comprising NaCl” that the art recognized sodium chloride (NaCl) as “having a stabilizing effect on insulin preparations” (col. 2, lines 53-54). [Note: Norup would be an anticipatory reference but for not expressly stating the Zn ions employed therein are Zn(II)]. Further, while Norup is drawn to insulin preparations comprising NaCl, Norup does not require any “additional buffering agents” (col. 2, lines 46-60), and only states the latter may be optionally added if desired (see col 4, lines 13-16); the only additional required elements being glycerol or mannitol (see Examples I-VI), which like NaCl are not generally classified as buffers even if occasionally added to buffers for their own qualities. As such, Norup provides the rationale as to why Schlichtkrull would have used NaCl in the buffer-free insulin formulations, for increased stability with a generally neutral molecule not constituting a buffer per se.
Thus, claim 1 is rendered prima facie obvious over Schlichtkrull with evidentiary support from Robinson (Zn(II) as the Zn ion) and in view of Norup (NaCl in a buffer-free insulin formulation).
Instant claim 2: Schlichtkrull teaches aqueous pharmaceutical formulation (col. 1, l. 64).
Instant claim 3: Schlichtkrull teaches a pH 7-7.8 (col. 1, l. 56).
Instant claim 6: Schlichtkrull teaches insulin at 40U/mL (col. 3, line 40), teaching the instantly claimed insulin range of 10-1000U/mL.
Instant claim 7: The teachings of Schlichtkrull render obvious the instantly claimed ratio of Zn:Insulin (0.0100-0.0600/100 U of insulin) by teaching that Zn is to be “just sufficiently high to crystalize insulin” (col. 3, lines 59-61); in other words, just high enough to carry out Zn’s intended, art-recognized role and amounts there-around. [Note: See also Norup Table 1 (col. 4, lines 36-62) as to the Zn:Insulin ratios render the same obvious, with these ratios being art-recognized as result effective variables open to routine optimization.].
Instant claims 8-9: As for instant claims 8-9 and the concentration of NaCl to be added, while Schlichtkrull does teach NaCl at a concentration of 1.4% of total solution (Example 3 in col. 3) that solution also contained additional buffers. However, Norup fills this gap by teaching the use of NaCl in insulin aspart formulations without additional buffers, for the art-recognized rationale that NaCl has a stabilizing effect on insulin (col. 2, lines 53-54) and that NaCl is the preferred halogenide (col. 3, lines 20-21). As for instant claim 8, Norup expressly teach an insulin aspart (AspB28) formulation without additional buffers with a NaCl concentration of 34 mM (Table 2) which equates to 6.1 mg/mL (the conversion of mM to mg/mL is 1 mM = 0.180 mg/mL), falling directly in the NaCl concentration range of 0.01 to 15 mg/mL range of instant claim 8. Additionally, as for instant claim 9, Norup also expressly teach another insulin formulation (one of the other insulin options) without additional buffers with a NaCl concentration of 40 mM (Table 6) which equates to 7.2 mg/mL (the conversion of mM to mg/mL is 1 mM = 0.180 mg/mL), falling directly within the NaCl concentration range of 6.8 to 8.3 mg/mL of instant claim 9. The latter amount of 40 mM/7.2 mg/ml NaCl would have been obvious to employ equally with insulin aspart (AspB28) as Norup expressly teaches the preferred fast-acting insulin is insulin aspart (col. 3, line 35) with a halogenide concentration of 5-40 mM (col. 3, line 39). Therefore, since both Schlichtkrull and Norup teach insulin aspart formulations without additional buffers, it would have been prima facie obvious to use the 40 mM/7.2 mg/mL NaCl concentration of Norup in the insulin aspart formulation of Schlichtkrull for the art-recognized rationale that NaCl has a stabilizing effect on insulin. [Further, as for the full range concentration of the halogenide/NaCl, Norup teach 5-100 mM (col. 4, lines 24-25), which equates to mg/mL concentration of .9 to 18 mg/mL, which fully encompasses the NaCl concentration ranges of 0.01 to 15 and 6.8 to 8.3 mg/mL of instant claims 8-9. See also Examples I-VI, opening line in each, col. 4-8, that the insulin aspart or other insulin “[s]olutions containing varying amounts [or] varying concentrations of sodium chloride was/were prepared”. Therefore, Norup sets forth that the concentration of NaCl is a result effective variable where varying that amount would be expected to impact the stabilization of insulin and as such constitutes a routinely optimizable parameter.] Thus, instant claims 8-9 are prima facie obvious based on Schlichtkrull in view of Norup.
While the protamine of instant claim 1 is an optional but not required limitation that is required in instant claim 10 as protamine sulfate in a concentration form 0.1 to 0.5 mg/mL. Protamine is a fish protein long added to insulin preparations for its art-recognized use of delaying absorption of insulin. Schlichtkrull taught as early as 1963 the use of protamine in insulin formulations (e.g. col. 1, lines 20-26), but not the sulfate form or concentration thereof. Merely by example, Pedersen fills this gap by teaching an insulin apart formulation comprising protamine sulfate of 0.33 mg/mL (para [0248]), falling inside the instantly claimed range of 0.1 to 0.5 mg/mL and rendering prima facie obvious the use thereof in the insulin aspart formulation of Schlichtkrull, where Schlichtkrull also taught protamine use in insulin formulations.
Instant claim 11: Schlichtkrull does not teach the addition of any of the additional eight (8) buffers excluded in claim 11 and thus teaches instant claim 11.
Instant claims 12 and 21-23: Drawn to addition of one or more further active pharmaceutical ingredients including an antidiabetic agent(s). While Schlichtkrull does not per se teach the addition of such, Schlichtkrull also does not preclude or teach away such. In that respect, Norup (col. 3, lines 25-61) fills this gap by teaching that one or more fact acting analogues of human insulin such as further insulin aspart or lispro (B28 or B29 Asp, Lys) may be comprised in a formulation (col. 3, lines 28-31), thus rendering instant claims 12-16 and 21-25 prima facie obvious based on Schlichtkrull in view of Norup.
Instant claims 24-25: Drawn to the combination of fast-acting insulin and long acting insulin. Robinson teach that another label for fast-acting insulin is rapid-acting insulin, which fall under the umbrella of short-acting insulins (earlier part of para [0346])). Robinson expressly teach the art was routinely mixing the two: “In many cases, regimens that use insulin in the management of diabetes combine long-acting and short-acting insulin” (middle of para [0346]), namely for a better, more balanced control of glucose levels in diabetics. Robinson teach fast/rapid/short-acting insulins such as instantly claimed insulin aspart (see also para [0061] cited above) as para [0346] (opening): “Short-acting insulin preparations that are commercially available in the U.S. include regular insulin and rapid-acting insulins. Regular insulin has an onset of action of 30-60 minutes, peak time of effect of 1.5 to 2 hours, and a duration of activity of 5 to 12 hours. Rapid acting insulins, such as aspart (Humalog.RTM.)/lispro (Novolog.RTM.), have an onset of action of 10-30 minutes, peak time of effect of 30-60 minutes, and a duration of activity of 3 to 5 hours.” Robinson teach long acting insulins such as instantly claimed insulin detemir (with acylation)(para [0346]). Thus, it would have been prima facie obvious to combine the fast/rapid/short acting insulin aspart of Schlichtkrull with the long acting insulin detemir of Robinson, as the latter expressly teach the combination of fast/rapid/short-acting insulins such as aspart with long acting insulin such as detemir.
Instant claims 19-23, 29-32: Schlichtkrull teaches standard insulin aqueous formulation preparations (col. 1, lines 69-72), including the formulation in the form of a preparation (claims 1-2; e.g. as instantly claimed a kit or package under the broadest reasonable interpretation thereof); including the standard art-recognized uses of insulin, namely “treating diabetes”, which equally covers diabetes at a level of hyperglycemia and lowering glucose levels associated with diabetes (col. 1, lines 16-20) (see also evidentiary reference Robinson, also cited above, teaching standard treatment for hyperglycemia and impaired glucose tolerance, para [0285]).
As for Optional Protamine in Claim 1: As discussed above previously, Schlichtkrull teaches formulations comprising both insulin and protamine (see col. 1, lines 20-26).
Regarding the result effective variables open to routine optimization: The legal test for routine optimization requires a finding that a person having ordinary skill in the art would know how to adjust the parameters at issue "to determine the optimum parameters." Ecolab, Inc. v. FMC Corp., 569 F.3d 1335, 1350 (Fed. Cir. 2009); and MPEP §2143(A). Here in the old art of insulin formulation for better diabetic treatment, adjusting such variables to determine optimum parameters is the hallmark and standard within the industry.
Based on the teachings of the reference(s), one of ordinary skill in this art at the time of the invention, would have had the rationale and reasonable expectation of success in arriving at the claimed invention, as a whole; which is deemed prima facie obvious.
NOTE: Schlichtkrull is a 1963 reference at a time when few analogues or derivatives of insulin were in the market. However, that would not preclude later ordinary artisans fully understanding that what Schlichtkrull taught equally applied to the later evolution of insulin forms. Further, Schlichtkrull bears no teaching away that what applies therein would not equally apply to analogues or derivatives of insulin.
Schlichtkrull Ex. 2 and 3 used buffers. However, this does not remove the teachings of Schlichtkrull in other Ex.’s that do not contain buffers. A reference is good for all that it teaches include alternatives.
Schlichtkrull taught that insulin formulations could be produced that were stable without buffers. Thus, that which was shown cannot form the basis for a latter assertion of unexpected findings here, without something more or further evidence.
Thus, the prima facie case of obviousness is maintained as in the parent.
Post-RCE Response to New Claim Scope Amendments
As forth above, Pedersen et al. (US Pub. No. 2007/0010424, “Pedersen”) – the latter reference Pederen (see para’s 43, 59 (& especially section title thereof), 62, and 346-347) of which teach the instant newly amended claim scope to “non-natural, long-acting analogue” and/or derivative of insulin” (but not the species icodec as in instant claims 5, 14, 17-18, and 33) – as interchangeable with the formerly claimed rapid/fast/basal insulins.
Double Patenting – Modified, Necessitated by Amendment
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-3, 6-9, 11-13, 19-23 and 29-32 (but not 5, 14, 17-18, and 33 drawn to insulin icodec as no prior art was found thereon prior to the earliest effective filing date – but see 35 USC 112 1st Paragraph (pre-AIA ) New Matter/Written Description Rejection below) are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-12 of US Patent No. 9,839,675 (‘675) alone or in view of either US Patent No. 9895423 (‘423) or US Patent No. 9895425 (‘425) – and futher in view of Pedersen et al. (US Pub. No. 2007/0010424, “Pedersen”) – the latter reference Pederen (see para’s 43, 59 (& especially section title thereof), 62, and 346-347) of which teach the instant newly amended claim scope to “non-natural, long-acting analogue” and/or derivative of insulin” (but not the species icodec as in instant claims 5, 14, 17-18, and 33) – as interchangeable with the formerly claimed rapid/fast/basal insulins:
[0043] FIG. 2B is a schematic diagram showing the A-chain and the B-chain of human insulin and the disulfide bridges present in human insulin compared to long acting insulin analogues, glargine (SEQ ID NO: 91) and detemir (SEQ ID NO: 93).
Rapid and Long Acting Insulins
[0059] The dicarba analogues of insulin of the present invention may be rapid or long acting insulins. The activity of the insulin may be modulated by mutating the native amino sequence to disrupt the self association between monomers of insulin, or by modification of one or more amino acids of the native insulin sequence. The activity of the insulin may be modulated by mutating the native amino sequence or by modification of one or more amino acids of the native insulin sequence to disrupt the solubility of the insulin. These modifications are encompassed by the dicarba analogues of insulin of the present invention.
[0062] In direct contrast, intermediate- and long-acting insulin preparations display slower onsets of action and can often last up to 24 hours. Initial preparations involved altering the solubility profile of native insulin via complexation with zinc, or using additives such as protamine or phenol-like derivatives. This produced the original isophane insulin suspensions (NPH), Humulin N/L and Novolin N/L, which are absorbed slowly from the subcutaneous injection site. Unfortunately, use of these intermediate-acting insulin suspensions produces highly variable results, leading to inconsistent onset and duration of effect. More recently, however, sequence modification has been used to extend the duration of insulin action in a safe and reproducible manner. Two analogues, insulin glargine and detemir, are now available for commercial application (FIG. 2B). Insulin glargine exploits the reduced solubility of insulin at physiological pH to control release. Addition of two arginine residues to the C-terminus of the B-chain, in addition to a glycine substitution at A21, increases the isoelectric point of the native molecule and increases formulation stability of the peptide in acidic media. These structural alterations generate an analogue that precipitates in the presence of zinc at the site of subcutaneous injection, and then slowly and reproducibly solubilises to produce a steady supply of insulin at target tissues. Insulin detemir on the other hand, exerts its activity through the presence of a long fatty acid chain joined to the c-amino group of Lys.sub.B29. This allows reversible, non-covalent binding to albumin in serum, which produces a human insulin analogue that displays a flatter and significantly longer time-action profile when compared to the native molecule. Although many diabetic patients are now enjoying the convenience of these long-acting analogues, there is still a considerable desire to improve basal insulin treatments. Unfortunately, both insulin variants have significant draw-backs, with glargine showing enhanced IGF-I receptor binding affinity, and detemir possessing reduced in vivo potency. In addition, both these analogues fail to produce a 24 hour duration of action, and hyperglycemia is still a common occurrence with these basal treatments. These modifications to the native insulin sequence, and the corresponding dicarba analogues of insulin are encompassed by the present invention.
[0346] Presently, different forms of typically subcutaneously-administered insulin preparations have been developed to provide different lengths of activity (activity profiles), often due to ingredients administered with insulin, ranging from short or rapid activity (e.g., solutions of regular, crystalline zinc insulin for injection; semilente insulin (prompt insulin zinc suspension); intermediate activity (e.g., NPH (isophane insulin suspension; lente (insulin zinc suspension; lente is a mixture of crystallized (ultralente) and amorphous (semilente) insulins in an acetate buffer); and slow activity (ultralente, which is extended insulin zinc suspension; protamine zinc). Short-acting insulin preparations that are commercially available in the U.S. include regular insulin and rapid-acting insulins. Regular insulin has an onset of action of 30-60 minutes, peak time of effect of 1.5 to 2 hours, and a duration of activity of 5 to 12 hours. Rapid acting insulins, such as aspart (Humalog.RTM.)/lispro (Novolog.RTM.), have an onset of action of 10-30 minutes, peak time of effect of 30-60 minutes, and a duration of activity of 3 to 5 hours. Intermediate-acting insulins, such as NPH (neutral protamine Hagedorn) and Lente insulins (insulin zinc suspension), have an onset of action of 1-2 hours, peak time of effect of 4 to 8 hours, and a duration of activity of 10 to 20 hours. In the case of long-acting insulins, Ultralente insulin has an onset of action of 2-4 hrs, peak time of effect of 8-20 hours, and a duration of activity of 16 to 24 hours, while Glargine insulin has an onset of action of 1 to 2 hours, a duration of action of 24 hours but no peak effect. There are over 180 individual insulin preparations available world-wide. Approximately 25% of these are soluble insulin (unmodified form); about 35% are basal insulins (mixed with NPH or Lente insulins, increased pl, or isoelectric point (insulin glargine), or acylation (insulin detemir); these forms have reduced solubility, slow subcutaneous absorption and long duration of action relative to soluble insulins); about 2% are rapid-acting insulins (e.g., which are engineered by amino-acid change, and have reduced self-association and increased subcutaneous absorption); and about 38% pre-mixed insulins (e.g., NPH/soluble/rapid-acting insulins; these preparations have the benefit, e.g., of reduced number of daily injections). In many cases, regimens that use insulin in the management of diabetes combine long-acting and short-acting insulin. It is contemplated that the dicarba insulin analogues of the present invention, and in particular the oral formulations which include the dicarba insulin analogues preferably together with a pharmaceutically acceptable delivery agent that facilitates absorption of the dicarba insulin analogue from the gastrointestinal tract, may be utilized in combination therapy to include an insulin that has rapid action, intermediate action, and/or slow action, as described above, in order to provide effective basal insulin levels in the, for example, diabetic patient. It will be appreciated that the combination therapy may comprise one or more dicarba insulin and one or more non-dicarba insulin such as for example any one of the commercially available insulins disclosed above. The rate of action of the insulin may be caused by virtue of its solubility, and/or by virtue of its half-life, etc. Thus, in alternative embodiments, the oral formulations of the present invention may be designed to provide the intermediate activity which is found with, e.g., a subcutaneously administered NPH insulin, or a slow action which is found with protamine zinc insulin. In each case, the oral formulations of the invention, which preferably include a pharmaceutically acceptable delivery agent which facilitates absorption of the insulin (as described herein) provide effective control of blood glucose levels, albeit for different time periods and with different plasma glucose time curves. Intermediate-acting and long-acting insulin may be prepared using methodologies known to those skilled in the art to provide a continuous level of insulin, similar to the slow, steady (basal) secretion of insulin provided by the normal pancreas. For example, Lantus.RTM., from Aventis Pharmaceuticals Inc., is a recombinant human insulin analog that is a long-acting, parenteral blood-glucose-lowering agent whose longer duration of action (up to 24 hours) is directly related to its slower rate of absorption. Lantus.RTM. is administered subcutaneously once a day, preferably at bedtime, and is said to provide a continuous level of insulin, similar to the slow, steady (basal) secretion of insulin provided by the normal pancreas. The activity of such a long-acting insulin results in a relatively constant concentration/time profile over 24 hours with no pronounced peak, thus allowing it to be administered once a day as a patient's basal insulin. Such long-acting insulin has a long-acting effect by virtue of its chemical composition, rather than by virtue of an addition to insulin when administered
[0347] In a preferred embodiment, administration of a pharmaceutical composition comprising a long-acting form of insulin (e.g. a therapeutic dicarba analogue of a long-acting form of insulin) is once or twice a day. In a preferred embodiment, administration of a therapeutic dicarba insulin providing short-acting insulin effect can be once, twice, three times, four times or more than four times daily, and can be at nighttime, in the morning and/or preprandially. In a more preferred embodiment, administration of the dosage form is preferably at nighttime or morning and three times preprandially, and more preferably is at nighttime and preprandially for breakfast, lunch and dinner. Preferably, the therapeutic dicarba insulin compositions are administered to such human patients on a chronic basis, e.g., for at least about 2 weeks. In certain preferred embodiments of the invention, the oral formulations of the invention provide two forms of insulin having different activity rates in order to simulate the biphasic release of insulin in non-diabetic humans. For example, such oral formulations may include a rapid-acting dicarba analogue (e.g. a therapeutic dicarba analogue of a rapid-acting insulin) together with a slow-acting dicarba analogue (e.g. a therapeutic dicarba analogue of a slow-acting insulin) so as to provide a first peak of insulin which occurs rapidly and is short-lived, followed by a second peak of insulin which occurs at a later time, but which preferably has a longer duration. In further alternatively preferred embodiments of the invention, the oral formulations of the invention include a rapid-acting dicarba analogue together with a secretagogue that promotes the secretion of insulin from the beta-cells at a time and to an extent which mimics the second phase release of insulin in non-diabetic humans.
Although the claims at issue are not identical, they are not patentably distinct from each other as set forth below.
Instant claims 1-3 relevant to the species combination of ‘675 claims 1-2 and 8-11 are read on by ‘675 as to the genus/subgenus of instant claims 1-4, including instantly claimed Zn(II), because the zinc chloride of ‘675 as read in light of the ‘675 specification expressly defines that the zinc chloride comprises Zn(II) ions: “Zinc Chloride Solution (which contains Zn(II)” (col. 20, lines 12-16). As ‘675 sets forth (and the instant identical specification) at the outset what matters is not the insulin, any insulin, analogue or derivative may be used, what matters is the formulation combination of elements the insulin chosen is put into (see e.g. col. 2, lines 29-67). As for the remaining instant claims, see remaining claims of ‘675. Further:
Instant claim 5 is rendered prima facie obvious by claim 1 of ‘675 as read in light of the ‘675 specification (col. 6, lines 11-20), where the “pharmaceutical formulation” as instantly claimed is defined as fully interchangeable/substitutable with either fast acting insulins specifically citing insulin aspart as in ‘675 claim 1 or the long-acting insulins specifically citing detemir and degludec as in instant claim 5. Thus, rendering the selection thereof by the skilled artisan viewing ‘675 in the instant pharmaceutical formulation as interchangeable and prima facie obvious.
Instant claim 6 is rendered prima facie obvious by claim 1 of ‘675 which while silent as to the units (U or concentration) of insulin per mL, as read in light of the specification defines that any insulin employed therein will be in the concentration range of 10 U/mL to 1000 U/mL, the full breadth and scope of that claimed in instant claim 6 (col. 4, lines 6-11).
Instant claim 7 is rendered prima facie obvious by claim 1 of ‘675 on each of the same grounds set forth in full as to instant claim 17 below relevant to Zn(II). Summarized here as to instant claim 7 claims 0.0100 to 0.0600 mg Zn(II)/100 U or 1 mL of insulin (note: the U or units (concentration) of insulin always per 1 mL; see ‘675 claim 6 and col. 4, lines 25-31). ‘675 claim 1 claims 0.04087 mg/mL of zinc chloride which as discussed above relevant to instant claim 1, the zinc chloride of ‘675 as read in light of the ‘675 specification expressly defines that the zinc chloride comprises Zn(II) ions: “Zinc Chloride Solution (which contains Zn(II)” (col. 20, lines 12-16). Further, as discussed below as to instant claim 17, ‘675 defines that the amount of zinc chloride added to solution equates to the amount Zn(II) in final solution (see col. 21, lines 29-30 as evidenced from Table 2 in col. 60, lines 55 to 63). Thus, ‘675 claiming 0.04087 mg/mL of zinc chloride renders prima facie obvious as read in light of the ‘675 specification that the final solution of ‘675 would equally contain 0.04087 mg/mL (or per 100 U) 0.04087 mg. Zn(II) ions, which falls right in the middle of that Zn(II) range claimed in instant claim 7.
Instant claims 8, 9 and 11 are equally read upon by ‘675, as evidenced in claims 1-2 and 4-12 of the latter.
Instant claims 12-14, as to one or more “further active pharmaceutical ingredients” are rendered prima facie obvious by claims 5-7 of ‘675 where the kit may comprise in “one package” which includes the formulation of ‘675 claim 1 and “at least one further active pharmaceutical ingredient” which could end yielding – once in the kit – a “pharmaceutical formulation” in that “one package” of claims 5-7 of ‘675. Claim 7 of ‘675 like instant claim 14, defines what those further ‘active’ pharmaceutical ingredients are, including insulin or analogues or derivatives thereof (note: this is in contrast to instant claims 10 and 18 discussed below which are not drawn to ‘active’ ingredients and which find no obviousness rationale based on the claims of ‘675). Under the broadest reasonably interpretation of claims 12-14, this could even be further insulin aspart, as claimed in ‘675 claim 1. Thus, it would have been prima facie obvious to formulate the pharmaceutical formulation of claim 1 of ‘675 with at least one further active pharmaceutical ingredient based on the kit of claims 5-7 of ‘675, as fully contemplated and supported as read in light of the ‘675 specification (col. 6, lines 11-20), which defines that the fast acting insulin is aspart, lispro or glulisine and the long acting insulin is detemir or degludec, which may be administered alone or in combination.
Instant claims 19-32 drawn to standard methods of use and products employed therein is equally rendered prima facie obvious over the same in ‘675.
It is noted that in a previous parent application (U.S. Patent Application No. 17/002,063), applicant had not challenged the double patenting rejection and was prepared to file the necessary terminal disclaimer over parent US Patent No. 9,839,675.
Post-RCE Response to New Claim Scope Amendments
As forth above in the obviousness rejection under 35 USC 103, the teachings of Pedersen et al. (US Pub. No. 2007/0010424, “Pedersen”) are also applied here – the latter reference Pederen (see para’s 43, 59 (& especially section title thereof), 62, and 346-347) of which teach the instant newly amended claim scope to “non-natural, long-acting analogue” and/or derivative of insulin” (but not the species icodec as in instant claims 5, 14, 17-18, and 33) – as interchangeable with the formerly claimed rapid/fast/basal insulins.
Claim Rejections - 35 USC § 112 1st Paragraph – Written Description (New Matter, Lack of Possession)
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 5, 14, 17-18, and 33 are rejected under 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.
This is a new matter rejection as there is no ipsis verbis support for the term/name icodec anywhere in the specification as filed. Further, there is insufficient guidance found for PHOSITA to have been guided/led by any of the chemical structure/formula permutations that would have led PHOSITA to arrive at the post-AIA ultra-long acting insulin icodec (which is a product of Novo Nordisk, not the instant applicant Sanofi). Thus, without further evidence, there is no support found for this term/name nor it’s now known chemical structure/formula rendering claims 5, 14, 17-18, and 33 new matter and lacking written description.
Conclusion
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/MAURY A AUDET/Primary Examiner, Art Unit 1654
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