Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of Claims
Claims 21,23,25-26,28-30,32,34 and 37-41 are pending in the instant application. Claims 39-41 are new claims where claim 39 is drawn to the elected invention. Claims 40-41 are withdrawn and do not encompass the originally presented language and examined subject matter. Claims 25-26,28-30,32 and 40-41are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
An action on the merits of claims 21,23,34 and 37-39 is contained herein.
Information Disclosure Statement
The examiner has considered the information disclosure statement filed most recently filed of record.
Status of Rejections
35 USC § 103
The rejection of claims 21,23,34 and 37-39 is maintained.
Applicant’s arguments, see Remarks, 9/9/2026, with respect to the rejection set forth in the Final Office Action mailed 3/9/2026, have been fully considered but are not found persuasive.
To reiterate the rejection of record, the claimed invention is drawn to a process of making a lyophilized pharmaceutical composition of the besylate salt of methyl 3-[(4S)-8-bromo-1 -methyl-6-(pyridine-2-yl)-4H-imidazo[ 1,2-a] [ 1,4]benzodiazepin-4-yl]propanoate (note that the free base is also known as Remimazolam in the art -a short acting benzodiazepine). The excipients included in the composition consisting of dextran 40 and lactose in specified ratios and weight amounts to afford the compositions. Dependent claims recite other inherent characteristics of the claimed compositions such as reconstitution times, pH, and reaction temperatures associated with the lyophilization process.
Feldman et al. (US Patent 7,160,880) taught the free base (methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[ 1,2-a] [ 1,4]benzodiazepin-4-yl]propanoate, from now on referred to as Remimazolam), see col. 45, example Ic-8. Feldman also taught generically that pharmaceutically acceptable salts (including the claimed besylate which is also known as benzenesulfonic) and lyophilized compositions thereof may readily be prepared for these classes of compounds (see col. 51, lines 31-42 for salts thereof, and col. 52, lines 8-15 for compositions).
At the time the invention was conceived, it was well documented in the art that the free base of Remimazolam was unstable at higher temperatures and known to decompose readily (see Tilbrook et al. WO 2008/007071, page 2, 1st paragraph). Tilbrook also discovered that Remimazolam formed highly crystalline salts (some amorphous, see Table 11, page 21) when converted to the besylate (benzenesulphonic acid) salt that were readily isolated and showed good stability and low hygroscopicity (see page 2, 2nd paragraph). Lastly similar to Feldman, lyophilized preparations are suggested. The document also provides some useful agents as an initial starting point to be used in the lyophilized formulation either alone or in combination or again that the compounds may be presented as lyophilized solids (see page 8, 3rd, 4th paragraph). Note that Tilbrook simply reinforces what is taught in Feldman regarding preparing salts of Remimazolam and lyophilized preparations thereof.
Therefore, there are recognized flaws regarding the instability of Remimazolam and the aforementioned documents explicitly teach how to prepare salts and formulations thereof of the latter for medicinal use to circumvent this problem. In particular, since Tilbrook discloses that the besylate salt possessed improved stability compared to the free base, it would have been viewed as a “lead compound” for further optimization, formulation, and development. The question that now remains is why one skilled in the art would have sought out to use dextran and another disaccharide such as lactose as excipients in these lyophilized formulations. In regard to the latter, Baheti et al. cures this deficiency.
Baheti et al. teach that 67% of marketed lyophilized formulations of small molecules contain excipients, with a significant number of those comprising bulking agents such as sugars or mixtures thereof (see Figure 4 on page 43 and table 1 at page
44). The document teaches how the process of lyophilization is routinely carried out in the art using excipients (see Introduction section, pages 41-42). Common excipients used in lyophilized formulations are shown below and at page 46 of the document:
PNG
media_image1.png
891
1009
media_image1.png
Greyscale
. It is stated that mannitol and glycine are the most commonly used excipients in this class followed by glucose, sucrose, lactose, trehalose, and dextran (see page 46, left column):
PNG
media_image2.png
195
753
media_image2.png
Greyscale
. Furthermore, the document provides a comparative example as to how lactose was shown to be a superior excipient compared to mannitol in the hydrolysis and degradation rates of methylprednisolone sodium succinate (a drug also containing an ester moiety and several fused ring systems). Attributing the latter to the hygroscopic nature of lactose in decreasing the amount of water in the environment of the drug (see page 46, right column and page 49, left column, first few sentences). Thus the ability of lactose to be utilized as an excipient for the stabilization of ester groups prone to hydrolysis in these compositions is also well documented.
Again, the excipients may be used alone or in combination as stated previously in Tilbrook and the examples in Table 1 of Baheti. Interestingly, the majority of the above bulking agents were explored extensively in the instant application and the compositions eventually tested for their physical and chemical properties (see Figure 4 of drawings):
PNG
media_image3.png
492
709
media_image3.png
Greyscale
. It is noteworthy to point out that the use of mannitol alone (formulation 5) showed a significant increase in degradation (hydrolysis of the ester group) when compared to employing lactose (formulations 2-4) which is consistent with the teachings in Baheti. Thus, lactose would have been a focal point for further exploration out of the already finite list of preferable excipients to choose from.
As described previously, preparing pharmaceutical salts and/or compositions thereof of old compounds are known improvement techniques for getting a more useful version of the pharmaceutical, and that the improvement is of a predictable nature, as is seen by the success reported in the various secondary references. Thus, it would have been obvious to one of ordinary skill in the pharmaceutical art to have applied these known improvement techniques in the same way to the compound of the primary reference to obtain the results reasonably predictable from the secondary references. See e.g. KSR International Co. v. Teleflex Inc., 1385, 1396; Ruiz v. AB Chance Co., 69 USPQ2d 1686; In re Nilssen, 7 USPQ2d 1500; Pfizer, Inc. v. Apotex, Inc. 82 USPQ2d 1321.
Thus, based on the preponderance of evidence in the art suggesting the preparation of stable lyophilized preparations of the besylate salt of Remimazolam (where the besylate salt would have in itself been viewed as a lead compound) for medicinal use and a preferred finite list (approximately 7 or so) of common pharmaceutical excipients in said preparations; one skilled in the art would have readily arrived at the claimed method of preparation and could have routinely verified these properties via routine methods of characterization. Limitations citing specified ratios/weight of active agent and excipients are not significant enough to tip the scales toward patentability and are considered routine optimization by one skilled in the art. Generally, differences in the latter will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such 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). Additionally, claims reciting inherent characteristics of the claimed compositions do not render said compositions patentable since one skilled in the art would have only needed to verify these properties via routine experimentation.
Applicants have amended the claims to be representative of the data disclosed below:
PNG
media_image4.png
156
690
media_image4.png
Greyscale
and subsequently centered their arguments on said data suggesting that the recited reconstitution times and/or physical properties of the resulting compositions were unexpected and unpredictable.
As stated previously in the previous office action that notwithstanding the arguments of unexpected results; the preponderance of evidence in the art suggesting the method and preparation of stable lyophilized preparations of the besylate salt of Remimazolam outweighs any unexpected findings. See MPEP 2145, Evidence pertaining to secondary considerations must be taken into account whenever present; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ("the record establish[ed] such a strong case of obviousness" that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) ("given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion" of obviousness); and Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988).
Additionally as stated in the Appeal #: 2020006629 decision, the Board also commented on the concept of unpredictability that was previously argued by Applicant:
PNG
media_image5.png
698
674
media_image5.png
Greyscale
Thus these arguments continue to not be found persuasive by the examiner.
Even despite the latter, the arguments presented by Applicant including the declaration filed 9/9/2026 are not convincing.
As stated prior by the examiner, upon inspection from the very limited range of formulations tested in the table, the % ratios of these excipients to the active compound “(L+D):R” appear to have a negligible effect (see last three entries for example 013-015 wherein the reconstitution times are similar wherein the dextran to lactose ratios are held constant). This trend is also observed primarily in entries 010-012 with the exception of one outlier. Thus based on the information above it appears varying the L/D excipient to active compound % ratio is not significant. Even a vis a vis comparison of entries 010 and 013 wherein the dextran to lactose ratios are different but the other variable is held constant, a time of 48s to 39s is observed. The claims now require that the encompassed formulations of claim 21 must meet the reconstitution time of less than 1 minute where the majority of these formulations meet that requirement with the exception of 011-012 that have times a few seconds outside this timeframe. How can the aforementioned data based on a few ratios be shown to be vastly superior to any other combination of dextran/lactose ratios outside the scope of what is shown? Applicants argue that “every extra second” is valuable in terms of drug reconstitution time (see page 9 of arguments) but the examiner is not convinced that a few seconds difference is a tangible difference in terms of obviating a strong case of obviousness in the instant case without additional supporting evidence.
Applicants also argue from the most recent declaration the following: “He explicitly states that because of the consistently faster reconstitution of formulations 013 to 015 he is "convinced that further formulations in that range, with (L+D):R ratios other than those specifically listed, would show a practically meaningful improvement in a pairwise comparison as well." (see page 10 of most recent arguments).
The aforementioned statement is not supported by any further additional evidence submitted by Applicant. Rebuttal evidence and arguments can be presented in the specification, In re Soni, 54 F.3d 746, 750, 34 USPQ2d 1684, 1687 (Fed. Cir. 1995), by counsel, In re Chu, 66 F.3d 292, 299, 36 USPQ2d 1089, 1094-95 (Fed. Cir. 1995), or by way of an affidavit or declaration under 37 CFR 1.132, e.g., Soni, 54 F.3d at 750, 34 USPQ2d at 1687; In re Piasecki, 745 F.2d 1468, 1474, 223 USPQ 785, 789-90 (Fed. Cir. 1984). However, arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
Therefore, based on the preponderance of evidence presented by the examiner and recent decisions by the Board in the parent case the rejection is maintained.
New Objections and Rejections
Claim Objections
Claims 21,23,34 and 37-38 are objected to because the instant claims possess non-elected subject matter. Newly submitted claim 21 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: The elected invention of claim 21 recited that the ratio of dextran and lactose to Remimazolam is between about 5:1 and 7:1. The instant claims appear to be broader in scope wherein the ratio is stated to be “from 4.4:1 to 8.8:1”. As stated previously in the prosecution history, the term “about” is not defined within the disclosure or the instant claims. Thus, the formulations could possibly encompass % ratios of dextran and lactose outside of what is recited in the claim (e.g. ratios below 5:1, greater than 7:1, etc.) to a certain degree. The lower and higher limits now presented may not necessarily fall within the language presented at time of examination with respect to “about”. Thus, without any guidance to confirm the latter it is viewed to be outside the scope of what was originally presented. Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, the language is objected to as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03. Correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 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.
Claim 39 is rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Feldman et al. (US Patent 7,160,880) in view of Baheti et al. (Journal of Excipients and Food Chem. 2010, 1, 41-54) and Tilbrook et al. WO 2008/007071 (-the latter two both mentioned in IDS).
The claimed invention is drawn to a process of making a lyophilized pharmaceutical composition of the besylate salt of methyl 3-[(4S)-8-bromo-1 -methyl-6-(pyridine-2-yl)-4H-imidazo[ 1,2-a] [ 1,4]benzodiazepin-4-yl]propanoate (note that the free base is also known as Remimazolam in the art -a short acting benzodiazepine). The excipients included in the composition consisting of dextran 40 and lactose in specified ratios and weight amounts to afford the compositions. Dependent claims recite other inherent characteristics of the claimed compositions such as reconstitution times, pH, and reaction temperatures associated with the lyophilization process.
Feldman et al. (US Patent 7,160,880) taught the free base (methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridine-2-yl)-4H-imidazo[ 1,2-a] [ 1,4]benzodiazepin-4-yl]propanoate, from now on referred to as Remimazolam), see col. 45, example Ic-8. Feldman also taught generically that pharmaceutically acceptable salts (including the claimed besylate which is also known as benzenesulfonic) and lyophilized compositions thereof may readily be prepared for these classes of compounds (see col. 51, lines 31-42 for salts thereof, and col. 52, lines 8-15 for compositions).
At the time the invention was conceived, it was well documented in the art that the free base of Remimazolam was unstable at higher temperatures and known to decompose readily (see Tilbrook et al. WO 2008/007071, page 2, 1st paragraph). Tilbrook also discovered that Remimazolam formed highly crystalline salts (some amorphous, see Table 11, page 21) when converted to the besylate (benzenesulphonic acid) salt that were readily isolated and showed good stability and low hygroscopicity (see page 2, 2nd paragraph). Lastly similar to Feldman, lyophilized preparations are suggested. The document also provides some useful agents as an initial starting point to be used in the lyophilized formulation either alone or in combination or again that the compounds may be presented as lyophilized solids (see page 8, 3rd, 4th paragraph). Note that Tilbrook simply reinforces what is taught in Feldman regarding preparing salts of Remimazolam and lyophilized preparations thereof.
Therefore, there are recognized flaws regarding the instability of Remimazolam and the aforementioned documents explicitly teach how to prepare salts and formulations thereof of the latter for medicinal use to circumvent this problem. In particular, since Tilbrook discloses that the besylate salt possessed improved stability compared to the free base, it would have been viewed as a “lead compound” for further optimization, formulation, and development. The question that now remains is why one skilled in the art would have sought out to use dextran and another disaccharide such as lactose as excipients in these lyophilized formulations. In regard to the latter, Baheti et al. cures this deficiency.
Baheti et al. teach that 67% of marketed lyophilized formulations of small molecules contain excipients, with a significant number of those comprising bulking agents such as sugars or mixtures thereof (see Figure 4 on page 43 and table 1 at page
44). The document teaches how the process of lyophilization is routinely carried out in the art using excipients (see Introduction section, pages 41-42). Common excipients used in lyophilized formulations are shown below and at page 46 of the document:
PNG
media_image1.png
891
1009
media_image1.png
Greyscale
. It is stated that mannitol and glycine are the most commonly used excipients in this class followed by glucose, sucrose, lactose, trehalose, and dextran (see page 46, left column):
PNG
media_image2.png
195
753
media_image2.png
Greyscale
. Furthermore, the document provides a comparative example as to how lactose was shown to be a superior excipient compared to mannitol in the hydrolysis and degradation rates of methylprednisolone sodium succinate (a drug also containing an ester moiety and several fused ring systems). Attributing the latter to the hygroscopic nature of lactose in decreasing the amount of water in the environment of the drug (see page 46, right column and page 49, left column, first few sentences). Thus the ability of lactose to be utilized as an excipient for the stabilization of ester groups prone to hydrolysis in these compositions is also well documented.
Again, the excipients may be used alone or in combination as stated previously in Tilbrook and the examples in Table 1 of Baheti. Interestingly, the majority of the above bulking agents were explored extensively in the instant application and the compositions eventually tested for their physical and chemical properties (see Figure 4 of drawings):
PNG
media_image3.png
492
709
media_image3.png
Greyscale
. It is noteworthy to point out that the use of mannitol alone (formulation 5) showed a significant increase in degradation (hydrolysis of the ester group) when compared to employing lactose (formulations 2-4) which is consistent with the teachings in Baheti. Thus, lactose would have been a focal point for further exploration out of the already finite list of preferable excipients to choose from.
As described previously, preparing pharmaceutical salts and/or compositions thereof of old compounds are known improvement techniques for getting a more useful version of the pharmaceutical, and that the improvement is of a predictable nature, as is seen by the success reported in the various secondary references. Thus, it would have been obvious to one of ordinary skill in the pharmaceutical art to have applied these known improvement techniques in the same way to the compound of the primary reference to obtain the results reasonably predictable from the secondary references. See e.g. KSR International Co. v. Teleflex Inc., 1385, 1396; Ruiz v. AB Chance Co., 69 USPQ2d 1686; In re Nilssen, 7 USPQ2d 1500; Pfizer, Inc. v. Apotex, Inc. 82 USPQ2d 1321.
Thus, based on the preponderance of evidence in the art suggesting the preparation of stable lyophilized preparations of the besylate salt of Remimazolam (where the besylate salt would have in itself been viewed as a lead compound) for medicinal use and a preferred finite list (approximately 7 or so) of common pharmaceutical excipients in said preparations; one skilled in the art would have readily arrived at the claimed method of preparation and could have routinely verified these properties via routine methods of characterization. Limitations citing specified ratios/weight of active agent and excipients are not significant enough to tip the scales toward patentability and are considered routine optimization by one skilled in the art. Generally, differences in the latter will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such 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). Additionally, claims reciting inherent characteristics of the claimed compositions do not render said compositions patentable since one skilled in the art would have only needed to verify these properties via routine experimentation.
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 BRIAN E MCDOWELL whose telephone number is (571)270-5755. The examiner can normally be reached on 8:30-6 MF.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIAN E MCDOWELL/Primary Examiner, Art Unit 1624
