Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 4, 9-11, 15-42 are cancelled.
Claim 50 is new.
Claims 1-3, 5-8, 12-14 and 43-50 are pending.
Withdrawn rejections
Applicant's amendments and arguments filed 5/22/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
Claims 1-3, 5-8, 12-14 and 43-50 are rejected under 35 U.S.C. 103(a) as being unpatentable over Cancer Network (Consider High Dose Melphalan as Standard Conditioning for Multiple Myeloma February 2000;volume 9(2): 3 pages; IDS filed 8/30/22) and Thompson et al. (WO2004024126) and Ma et al. (International Journal of Pharmaceutics 1999;189:227-234; IDS filed 8/30/22) and ALKERAN® (Prescribing Information 2002 11 pages; IDS filed 8/30/22) and Stella et al. (Toxicologic Pathology, 36:30-42, 2008) and Strickley, RG (Pharmaceutical Research, Vol. 21, No. 2, February 2004; 201-230).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Applicant claims for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a medical/pharmaceutical oncology research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from oncology medicine, oncology drug formulation and chemistry— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
With regard to instant claims 1-3, the Cancer Network teaches a conditioning regimen in patients diagnosed with the neoplastic disorder multiple myeloma (myeloma is synonymous with multiple myeloma), where 140 mg/m2 or 200 mg/m2 of melphalan (Alkeran) is administered (page 1, paragraphs 1 and 2). The patient is therefore a subject suffering from a neoplastic disorder. Cancer Network teaches that high dose melphalan alone should be the standard conditioning regiment for autologous transplantation in patients with newly diagnosed multiple myeloma (page 3, first paragraph) and higher doses are feasible (last paragraph page 3).
With regard to instant claims 1-3, 8 and 45-49, ALKERAN® teaches that ALKERON® for Injection a freeze-dried powder of melphalan hydrochloride in one vial and sterile diluent in another vial (Page 2, lines 29-33) and is indicated for the palliative treatment of patients with multiple Myeloma (page 4, lines 94-96), hence a neoplastic disorder. It is supplied as a single use vial with 50 mg melphalan hydrochloride in one vial and the other diluent vial is substantially free of alcohol (only 0.52 mL in 10 mL water for injection) (page 2, lines 29-33). ALKERAN® teaches that a pediatric patient survived a 254-mg/m2 overdose, thus teaching the treatment of pediatric patients (page 9, line 230-231). ALKERAN® teaches that the melphalan powder must be reconstituted to make a 5 mg/mL solution which is then diluted in 0.9% sodium chloride, which is a saline solution, to a concentration of not greater than 0.45 mg/mL which is administered by injection over 15-60 minutes into the patient, thus reading on systemic limb perfusion, and provides palliative treatment of multiple myeloma (pages 9, line 253-page 10, line 260 Preparation for Administration/Stability). ALKERAN® also teaches to keep the time between reconstitution/dilution and administration to a minimum and not to refrigerate (page 10, lines 263-269).
Regarding claims 1, 5-8, 13-14 and 43-49, Ma et al. teach injectable melphalan formulations utilizing SBE7-β-CD, which the Examiner interprets to be a species of instant Formulas I and II as shown below:
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with a degree of substitution of 4-8, to improve the current melphalan hydrochloride injectable formulation of ALKERAN® where a major concern with ALKERAN® is the co-solvents (alcohols as taught by Ma et al. Page 228, left column and ALKERAN® above) that cause significant cell disruption (page 228, right column Biocompatibility issues) and chemical stability (Abstract). Ma et al. teach that when cyclodextrins were used as diluents, the use of organic solvents can be eliminated and the shelf life greatly enhanced (Abstract). Ma et al. teach that “(SBE)7m-b-CD (Captisol™), may be suitable for parenteral use due to their low systemic toxicity. Both (SBE)7m-b-CD and HP-b-CD are excellent solubilizers and stabilizers for melphalan based on our previous studies” (page 228, right column). Ma et al. teach lyophilized solid powder (Page 229 2.5 (SBE)7m-b-CD used as the freeze-drying excipient in a melphalan formulation).
Further regarding claims 1, 7, 43-45, Ma et al. teach compositions comprising 10 mL aqueous 0.1 M (SBE)7m- β-CD, which is about 0.125 M, plus 50 mg melphalan, which is between 25-125 mg melphalan, and comprising 100 mL aqueous 0.1 M (SBE)7m- β-CD plus 0.5 g melphalan. (p. 228, col. 1; p. 229, Sec. 2.3 and 2.5) Ma et al. teach the molecular weight of the (SBE)7m- β-CD is 2248.64. Therefore, 1 L of 0.1 M (SBE)7m- β-CD would have 224.864 g of (SBE)7m- β-CD. 100 mL would use 22.4864 g and 10 mL would use 2.24864 g. When compared to 0.5 g and 50 mg respectively this is a ratio of about 45 to 1, (SBE)7m- β-CD to melphalan, which is sufficiently close to 50:1 or about 54:1 such that the same properties are expected. See MPEP 2144.05(I): “Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
With regard to instant claim 1, Ma et al. teaches diluting the compositions in aqueous 0.9% NaCl for injection (page 229, right column).
Regarding claim 1, Ma et al. teach a shelf life of the composition reconstituted with SBE of 17.4 hours (T-90%) ostensibly at room temperature (Table 1, page 230; Figure 1), thus taking 17.4 hours to reach 90% and appears to degrade by 4% or less at 25 C within 10 hours of dilution or less than 2% at about 25 C within 5 hours, especially when the cyclodextrin is the same as claimed and it is the same active agent. Ma et al. report stable lyophilized powder formulations of melphalan/(SBE)7m-β-CD (page 233, lower right column) and stable over a period of 1 year (page 234, lower left column) and no precipitation of reconstituted Alkeron upon refrigeration (page 232, 3.1 right column). Ma et al. teach on page 233, left column:
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With regard to claims 1, 5-7, 43-44 and 50, Thompson et al. guide the artisan to Captisol cyclodextrin where n = 6.0-7.1, (Page 4, 3rd paragraph through page 5) as shown below:
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Thompson et al. also studied SBE having about 6.5-7.5 degrees of substitution (Page 18, 2nd paragraph; page 19, 1st paragraph). Thompson et al. teach complexes of SBe7-β-CD in a weight ratio of derivatized cyclodextrin to active agent in excess of 100 or 1000 or even more (Page 35 1st through 3rd paragraphs) and where the drug can be melphalan (Page 55, 2nd paragraph). Thompson et al. teach: “Thus, the CD will generally be, but need not be, present in excess of the active agent. The amount of excess will be determined by the intrinsic solubility of the agent, the expected dose of the agent, and the binding constant for inclusion complexation between the specific drug (agent) and the specific CD derivative used.” (Page 35, 3rd paragraph).
Regarding claim 1, Stella et al. teach: “A number of workers have attempted to identify, prepare, and evaluate various CD derivatives with superior inclusion complexation and maximal in vivo safety for various biomedical uses. A systematic study led to SBE-β-CD (Captisol), a polyanionic variably substituted sulfobutyl ether of β-CD, as a non-nephrotoxic derivative and HP-β-CD, a modified CD developed by Janssen. SBE-β-CD and HP-β-CD have undergone extensive safety studies and are currently used in six products approved by the Food and Drug Administration (four for Captisol and two for HP-β-CD). They are also in use in numerous clinical and preclinical studies.” (Abstract and page 31, left column last paragraph).
Regarding claims 1, 5-7 and 50, Strickley is a review of commercially available oral and injectable solubilizing excipients including sulfobutylether-β-cyclodextrin (Abstract; Page 209, Table II “Captisol®”) where the sulfobutylether-β-cyclodextrin, has average degree of substitution: 6.5 and a MW = 2163 from Captisol (Table III, page 212). Strickley report that: “The newest cyclodextrin to be commonly used is sulfobutylether-β-cyclodextrin (Captisol, www.cydexinc.com, Overland Park, KS, USA, Table III). Captisol is very safe, chemically stable, water-soluble, and is an excellent solubilizing drug delivery technology for molecules in which it forms an inclusion complex.” (Page 224, left column 2nd paragraph).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Cancer Network is that Cancer Network do not expressly teach diluting 25-125 mg of lyophilized melphalan HCl powder and the cyclodextrin derivative in saline where the melphalan in the dilute pharmaceutical composition degrades by 4% or less at 25° C within 10 hours after the diluting as instantly claimed in a ratio of at least 50:1 cyclodextrin to melphalan, or 50:1 to about 100:1 about 54:1, and injecting that diluted composition into the patient to provide palliative treatment of multiple myeloma. This deficiency in Cancer Network is cured by the teachings of ALKERAN®, Thompson et al., Ma et al., Stella et al. and Strickley.
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to perform the method of Cancer Network by diluting 25-125 mg of melphalan HCl and the cyclodextrin derivative where the melphalan in the dilute pharmaceutical composition degrades by 4% or less at 25° C within 10 hours after the diluting as instantly claimed in a ratio of at least 50:1 cyclodextrin to melphalan, or 50:1 to about 100:1 about 54:1, and injecting into a patient to provide palliative treatment of multiple myeloma, as suggested by ALKERAN®, Ma et al., Thompson et al., Stella et al. and Strickley, and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because Cancer Network teaches using ALKERAN® in the method but Ma et al. have shown that ALKERAN® has serious problems and to overcome those problems Ma et al. have developed and injectable melphalan formulations utilizing SBE7-β-CD from Captisol to improve the current melphalan injectable formulation of ALKERAN®. Ma et al., Thompson et al., Stella et al. and Strickley all direct the artisan to Captisol. Strickley points to the ease of access of the SBE6.5-β-CD MW = 2163 from Captisol that is “an excellent solubilizing drug delivery technology” and Stella et al. also teach the desirable properties of Captisol, such as FDA approval, for the cyclodextrin as further motivation to select that product. Thus, the ordinary artisan would find it desirable to switch from ALKERAN® to the improved injectable composition of Ma et al. using (SBE)7m-β-CD (Captisol™), which is also known in the art as, Captisol SBE6.5-β-CD MW = 2163 for the cyclodextrin as suggested by Strickley and inject it into a patient with a reasonable expectation of success. Consequently, the ordinary artisan would employ the improved melphalan Captisol SBE7-β-CD composition of Ma et al. at a pH of 6 by diluting a composition with 25-125 mg of melphalan and a Captisol cyclodextrin derivative taught by Ma et al., Thompson et al. and Stella et al., and intravenously injecting the diluted pharmaceutical composition into the subject in need thereof for systemic palliative treatment of multiply myeloma as suggested by ALKERAN®. Regarding the weight ratio of at least 50:1 limitation, the Examiner has shown above that Ma et al. teach a weight ratio of about 45:1. And the Examiner has shown through the teachings of Thompson et al. to employ derivatized cyclodextrins such as SBE7-β-CD with the active agent melphalan where the weight ratio or molar ratio of the derivatized cyclodextrin to active agent can exceed 100 or more, hence 100:1. That reasonably provides a weight ratio range of 45:1 to greater than 100:1, which encompasses the claimed ranges of at least 50:1, 50:1 to 100:1 or about 54:1. See MPEP 2144.05(I): “A range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case.” It is then merely routine optimization by increasing the ratio of the cyclodextrin derivative to melphalan ratio to achieve the functional limitation of where the melphalan in the dilute pharmaceutical composition degrades by 4% or less at 25° C within 10 hours after the diluting with a reasonable expectation of success. Especially when Applicant also employs Captisol with an average MW of 2163 g/mol (Specification [0058-0059]; Examples 1-4, 8 and 10-13). Consequently, it appears the claimed functional parameters naturally flow from employing Captisol. Furthermore, pharmaceutical dose has been recognized as a result-effective parameter susceptible to routine optimization. See, e.g., Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed. Cir. 1989) (drug dosage limitations resulted from routine experimentation). From MPEP 2144/05 (II) (A): “[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)…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."). With any evidence of a criticality, adjusting the weight ratio is merely mechanical improvement, which expresses no patentable quality as there must be ingenuity over and above mechanical skill. Thus, the ordinary artisan would have a reasonable expectation of success because it is merely increasing the amount of cyclodextrin derivative in solution as suggested by Thompson et al. and arrive at the instantly claimed limitation where it is well-known in the art that increasing the amount of cyclodextrin concurrently increases the stability as taught by Ma et al. Especially when Thompson et al. teach and suggest weight ratios of cyclodextrin:active agent melphalan of 100 or more. Accordingly, the ordinary artisan would have a reasonable expectation of success in so doing.
2. The difference between the instant application and Cancer Network is that Cancer Network do not expressly teach storing the composition for about 0.5-12 hours prior to administering; the functional degradations properties or the Cmax or AUC that is at least 20% greater than an equivalent dose that lacks cyclodextrin derivative or bioavailability that is greater than an equivalent dose that lacks cyclodextrin derivative as instantly claimed. This deficiency in Cancer Network is cured by the teachings of Ma et al., Thompson et al., Stella et al. and Strickley.
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to perform the method of Cancer Network with the melphalan cyclodextrin derivative Captisol of Ma et al., Thompson et al., Stella et al. and Strickley where the composition is stored for about 0.5-12 hours prior to administering; the functional degradations properties or the Cmax or AUC that is at least 20% greater than an equivalent dose that lacks cyclodextrin derivative or bioavailability that is greater than an equivalent dose that lacks cyclodextrin derivative as instantly claimed, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because these functional properties are implicit in the melphalan SBE7-β-CD composition of Ma et al., Thompson et al., Stella et al. and Strickley where the sulfobutylether-β-cyclodextrin with a MW of 2163 and average degree of substitution of 6.5 is from Captisol. Applicant employs the same Captisol (See the specification [0058-0059]; Examples 1-4, 8 and 10-13). Therefore, administration of the Captisol composition suggested by Ma et al., Thompson et al., Stella et al. and Strickley, naturally has a Cmax and/or AUC that is at least 20% greater than an equivalent dose that lacks cyclodextrin derivative or bioavailability that is greater than an equivalent dose that lacks cyclodextrin derivative in the absence of evidence to the contrary. “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).” Regarding the limitation of storing the composition for about 0.5-12 hours prior to administering, it is the Examiner’s position that this is at the discretion of the ordinary medical artisan would have exercised sound medical judgment, policies, and practices as to when to store the composition until it is needed within medical guidelines and good practice, which would ostensibly be shortly after reconstitution such as within 30 minutes or several hours with a reasonable expectation of success.
3. The difference between the instant application and Cancer Network is that Cancer Network do not expressly teach all the neoplastic disorders of claim 2. However, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to perform the method of Cancer Network with the melphalan Captisol cyclodextrin derivative of Ma et al., Thompson et al., Stella et al. and Strickley on patients with any of the neoplastic disorders of claim 2, as suggested by ALKERAN® and Ma et al. and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because ALERAN® teaches that melphalan is an alkylating agent that is active against human neoplastic diseases (Page 1, lines 16-18) and Ma et al. teach that melphalan is an anti-neoplastic agent (Abstract). It is then merely judicious selection of known neoplastic disorders by the ordinary oncologist in this art to treat with the melphalan formulation of Ma et al., Thompson et al., Stella et al. and Strickley with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicant’s arguments filed on 5/22/26 have been carefully considered but are not persuasive.
Prior to considering Applicant’s remarks, the Examiner presents a summary of the prior art.
Treating neoplastic disorders such as multiple myeloma with melphalan is known in the art. Cancer Network teaches a conditioning regimen in patients diagnosed with the neoplastic disorder multiple myeloma (myeloma is synonymous with multiple myeloma), where 140 mg/m2 or 200 mg/m2 of melphalan (Alkeran) is administered.
Cyclodextrin-melphalan compositions were made to improve upon the art. Ma et al. teach injectable melphalan formulations utilizing SBE7-β-CD with a degree of substitution of 4-8 to improve the current melphalan hydrochloride injectable formulation of ALKERAN® where a major concern with ALKERAN® is chemical stability.
Pharmaceutical compositions of cyclodextrin derivative and an active agent such as melphalan in a weight ratio of at least 50:1 are known in the art. The art of Thompson et al. teach complexes of SBe7-β-CD in a weight ratio of derivatized cyclodextrin to active agent in excess of 100 or 1000 or even more.
Cyclodextrin derivatives with an average degree of substitution of about 6.5 are known in the art. Thompson et al. studied SBE having about 6.5-7.5 degrees of substitution. Strickley is a review of commercially available oral and injectable solubilizing excipients including sulfobutylether-β-cyclodextrin where the sulfobutylether-β-cyclodextrin, has average degree of substitution: 6.5 and a MW = 2163 from Captisol. Strickley and Stella et al. direct the artisan to the desirable Captisol cyclodextrin derivative.
On pages 6-7 of remarks, Applicant asserts that the rejection does not establish a reasonable expectation of success. Applicant argues that the Examiner’s reasoning “does not establish a reasonable expectation that a cyclodextrin-containing melphalan composition, after dilution with saline and injection, would deliver therapeutically effective melphalan for treating a subject suffering from a neoplastic disorder.” Furthermore, Applicant contends: “The issue is not whether melphalan was known to treat multiple myeloma, or whether cyclodextrins were known formulation excipients (which Applicant does not concede). The rejection is deficient because the cited references, alone or in combination, do not show that a person of ordinary skill in the art would have reasonably expected the proposed cyclodextrin containing melphalan composition to deliver therapeutically effective melphalan after the claimed
dilution and administration in amounts suitable to treat a neoplastic disorder.” The basis for Applicant’s position appears to rest in the teachings from Stella citing Rajewski where “"[a]t the concentrations needed to effect stabilization, the cyclodextrin formulation of the drug was completely ineffective."” Applicant concludes: “These references do not support the Examiner's allegation that increasing cyclodextrin concentration to increase formulation stability would necessarily preserver, much less predictably provide, therapeutically effective melphalan after administration as claimed.” Respectfully, the Examiner has a different perspective. The Rajewski reference teaches:
“If large excesses of cyclodextrin are present, they can lower the free fraction of drug and increase the fraction of drug in the complex form, thereby lowering the effectiveness of the agent (Scheme 3C) by pushing the equilibrium to the right, thus increasing the probability of greater nasolacrimal excretion of the complex.” (Page 1155, right column 2nd paragraph).
Ma et al. is not concerned with “greater nasolacrimal excretion of the complex” or ophthalmic drugs and neither would be the artisan employing the antineoplastic agent melphalan. Consequently, the Examiner can disregard the teachings of Stella and Applicant’s argument is not persuasive.
On page 7 of remarks, Applicant asserts: “Even if melphalan is allegedly "known as an antineoplastic compound," a POSA would not have reasonably expected that complexing it with a cyclodextrin would retain that activity.” However, Applicant cites no evidence to support that position and the art of record would suggest otherwise. Complexing melphalan with a cyclodextrin does not fatally alter the structure of uncomplexed melphalan, which is the active form. Applicant’s argument is not persuasive.
On page 8 of remarks, Applicant asserts: “The rejection also does not establish that the claimed post-dilution stability limitations would have been obvious or inherent.” Respectfully, the Examiner does not agree because the prior art directs the artisan to Captisol SBE6.5-β-CD MW = 2163 for the cyclodextrin derivative, which is exactly the same cyclodextrin derivate employed by Applicant. All Applicant has apparently done is test a well-known and desirable cyclodextrin derivative and report the stability post-dilution values. See MPEP 2112.01 II.COMPOSITION CLAIMS — IF THE COMPOSITION IS PHYSICALLY THE SAME, IT MUST HAVE THE SAME PROPERTIES
“Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).”
On pages 8-9 of remarks, Applicant asserts: “The Examiner's reasoning appears to rest on the premise that increasing cyclodextrin concentration would predictably increase melphalan stability until the claimed stability threshold is reached. But there is no disclosure in the references to support this allegation.” However, the Examiner’s position is based upon the prior art directing the artisan to the same cyclodextrin derivative Captisol SBE6.5-β-CD MW = 2163 for use in complexing melphalan in a weight ratio in excess of 100:1, where the increasing amount of Captisol SBE6.5-β-CD MW = 2163 would increase the stability accordingly resulting in the same amount of degradation at 10 hours at room temperature as claimed. Ma et al. employed a slightly different cyclodextrin derivative and therefore a variation in stability would be expected. Furthermore, Applicant’s observed stability is merely a difference in degree from that observed by Ma et al. and not a difference in kind. “It is the general rule that while the change in the proportions of a combination shown to be old, such as is here involved, may be inventive, such change must be critical as compared with the proportions used in prior processes, producing a difference in kind rather than degree.” In re Dreyfus, 73 F.2d 931, 934 (C.C.P.A. 1934). In the present case, there is an expectation of a time to 10% loss to take hours and that is what Applicant has demonstrated. While Applicant may have produced better results in terms of time to 10% loss than the prior art, that is not enough to sustain a patent. “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.” (In re Williams, 36 F.2d 436, 438, 17 C.C.P.A. (Patents) 718, 722). In the present case, the inventors merely used routine research methods to prove what was already believed to be the case. Scientific confirmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention. See Pharmastem v. Viacell, 491 F.3d 1342, 1364 (Fed. Cir. 2007): “Good science and useful contributions do not necessarily result in patentability.” Respectfully, Applicant’s arguments are not persuasive.
On page 9 of remarks, Applicant argues that the evidence is at least commensurate with the narrowed dependent claims. However, the independent claim 1 has no molecular weight or degree of substitution limitation to describe the cyclodextrin derivative and is only defined by the functional limitation. At best, new claim 50 introduces an average degree of substitution of about 6.5 but that value is already known in the art. While an average degree of substitution of about 6.5 may produce better results than prior inventions, such is not enough to sustain a patent because it is merely a difference in degree and not in kind. Additionally, the evidence shown by Applicant does not provide a reasonable basis for concluding that the untested embodiments encompassed by the claims would behave in the same manner as the tested embodiment. Therefore, Applicant’s findings are not commensurate in scope with the claimed subject matter.
On page 10 of remarks, Applicant contends that the rejection does not establish that the comparative pharmacokinetic limitations of claims 13 and 14 are inherent or expected. Applicant states: “The rejection does not identify prior-art pharmacokinetic evidence establishing these comparative limitations. Nor does the rejection identify any prior-art composition that is the same as the claimed composition and shown to necessarily produce the recited increase in Cmax or AUC relative to the claimed cyclodextrin-free comparator.” Respectfully, the Examiner has two comments. First, the Examiner is not equipped to measure the prior art pharmacokinetic parameters and the pharmacokinetic limitations are intimately connected with the Captisol SBE6.5-β-CD MW = 2163 cyclodextrin derivative, which is obvious over the combined references. Secondly, all Applicant did was administer the formulation and measure the resulting Cmax and AUC, which is a conventional measurement for the ordinary artisan in the pharmaceutical arts. Furthermore, melphalan’s inherent instability in aqueous solution is well-known (see Ma et al. page 227, right column last paragraph). Consequently, the ordinary pharmaceutical artisan readily grasps that a cyclodextrin formulation designed to increase the stability of melphalan in aqueous solution is going to have a Cmax and AUC greater than an equivalent does of melphalan lacking a stabilizing cyclodextrin derivative because of rapid spontaneous aqueous hydrolysis. Upon further inspection, Applicant appears to have no data to support the functional limitations. In looking to the specification for support, Applicant measured the AUC for SBE6.5-β-CD and CD-free formulations in whole blood and plasms. The results are shown below and in Figures 5A-5B:
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When taking into consideration the standard deviations, there is no difference. This is shown in the Figures:
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Example 17 was conducted on 3 patients [0198], a very small sample size, and pharmacokinetic data was obtained and presented in a table [0213, 0216]. However, the data lacks statistical analysis in order to have any probative value. Interestingly, Figure 6 provides standard deviation bars and shows overlap between the inventive composition and control as shown below:
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There does not appear to be any statistical difference between the inventive and comparative. Therefore, claims 13 and 14 are not patentable without more. The Examiner has very carefully considered Applicant’s arguments and data. The Examiner does not find the arguments or data persuasive. Respectfully, the claims remain rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
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