DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Acknowledgement of Receipt
Applicant’s Response, filed 11/19/2025, in reply to the Office Action mailed 8/19/2025, is acknowledged and has been entered. Claims 1, 5, 10, 15 and 16 have been amended. Claims 1, 3-7, 10-18 and 20-26 are pending, of which claims 23-26 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1, 3-7, 10-18 and 20-22 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. The rejections have been modified, necessitated by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-7, 10-18 and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. . The instant claims are directed to a sterile, non-pyrogenic, lyophilized pharmaceutical composition, comprising: i) macroaggregated albumin; ii) stannous chloride; iii) human serum albumin; and sodium chloride; wherein the macroaggregated albumin is stannous incorporated macroaggregated albumin and wherein the average particle size of the macroaggregated albumin particles is 20 um to 35 um when measured by optical microscopy and/or automated microscopy and image analysis; wherein at least 95% of the macroaggregated albumin particles are between 10 um to 70 um, less than 3% of the macroaggregated albumin particles in the lyophilized pharmaceutical composition are below 10 µm and none of the macroaggregated albumin particles are above 100 um when measured by optical microscopy and/or automated microscopy and image analysis; wherein the macroaggregated albumin particles have not more than 3% soluble and dispersed human serum albumin content, when measured by optical microscopy and/or automated microscopy and image analysis; wherein the lyophilized pharmaceutical composition is a single dose or a multiple dose composition: wherein the number of macroaggregated albumin particles in a single dose of the multi-dose lyophilized pharmaceutical composition is within the range of 300,000-700,000 and the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles between two single doses of the multidose lyophilized pharmaceutical composition is about 400,000 particles or less; and wherein the composition has a shelf-life of two years when stored at a temperature of 25°C.
With regard to the amended limitation wherein the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles between two single doses of the multidose lyophilized pharmaceutical composition is about 400,000 particles or less, the Response filed 11/19/2025 states that “Support for the amendments to the claims are found in the application as filed at Table V, which shows that four batches of the lyophilized composition have a particle count between 300,000, 300,000, 500,000 and 700,000, resulting in a difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles in two doses of the lyophilized pharmaceutical composition to be about 400,000 particles or less.” However, upon review it is noted that data provided in Table V, to which Applicant refers, is directed to radiolabeling of lyophilized MAA single dose vials, see Example 5, including three batches, Example 5.1, Example 5.2 and Example 5.3. The specification does not recite the claim language of the amended claims. It is noted that the with regard to particle number, the published specification recites: [0154] In one embodiment, the present invention provides a single dose kit comprising the pharmaceutical composition of X-J-MAA, wherein the number of macroaggregated particles in the kit is between 300,000 to 700,000. [0155] In another embodiment, the present invention provides a multiple dose kit comprising the pharmaceutical composition of X-J-MAA, wherein the number of macroaggregated particles in the kit is between 3,000,000 to 7,000,000. As such it is considered that the specification as filed does not provide support for the amended claim language, in particular with regard to multi-dose vials and “or less” language. This is a new matter rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-7, 10-18 and 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/939,951 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a sterile, non-pyrogenic, lyophilized pharmaceutical composition, comprising: i) macroaggregated albumin; ii) stannous chloride; iii) human serum albumin; and sodium chloride; wherein the macroaggregated albumin is stannous incorporated macroaggregated albumin and wherein the average particle size of the macroaggregated albumin particles is 20 um to 35 um when measured by optical microscopy and/or automated microscopy and image analysis; wherein at least 95% of the macroaggregated albumin particles are between 10 um to 70 um, less than 3% of the macroaggregated albumin particles in the lyophilized pharmaceutical composition are below 10 µm and none of the macroaggregated albumin particles are above 100 um when measured by optical microscopy and/or automated microscopy and image analysis; wherein the macroaggregated albumin particles have not more than 3% soluble and dispersed human serum albumin content, when measured by optical microscopy and/or automated microscopy and image analysis; wherein the lyophilized pharmaceutical composition is a single dose or a multiple dose composition: wherein the number of macroaggregated albumin particles in a single dose of the multi-dose lyophilized pharmaceutical composition is within the range of 300,000-700,000 and the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles between two single doses of the multidose lyophilized pharmaceutical composition is about 400,000 particles or less; and wherein the composition has a shelf-life of two years when stored at a temperature of 25°C. Claim 5 of the ‘951 Application is directed to a radiopharmaceutical composition comprising X-J-MAA, including MA, macroaggregated albumin particles wherein the average particle size of the macroaggregated albumin particles is 20-35 µm, at least 95% of the macroaggregated albumin particles are between 10 µm to 70 µm, not more than 3% particles are below 10 µm and no particle is larger than 100 µm. Dependent claim 14 is directed to a single dose kit comprising the single dose pharmaceutical composition of claim 5, wherein the number of macroaggregated particles in the kit is between 300,000 to 700,000. Dependent claim 15 is directed to a multiple dose kit comprising the pharmaccutical composition of claim 5, wherein the number of macroaggregated particles in the kit is between 3,000,000 to 7,000,000. Dependent claim 16 is directed to a sterile radiopharmaceutical composition, X-J- MAA prepared by a process comprising the steps of: i) preparing macroaggregated albumin (MAA) by: ia) mixing human serum albumin with a saline solution; ib) adjusting the pH between 8.0 to 12.0 with stirring at a rate of 200 to 500 rpm at 60-80°C; ic) cooling to 20 to 25°C with stirring at a rate of 200 to 400 rpm; id) adjusting the pH to 2.0 to 5.0 and sterile filtering the solution to obtain a filtrate; ie) adjusting the pH of the filtrate to 4.0 to 6.0 if) heating the solution at 50 to 80°C at stirring rate of 200 to 400 rpm and cooling to obtain a macroaggregated albumin; ig) optionally, reacting the macroaggregated albumin with stannous chloride for 10 to 20 minutes at 65 to 80°C to obtain stannated macroaggregated albumin (Sn-MAA) or conjugating macroaggregated albumin with a suitable chelating agent; and ih) optionally, introducing a chelating agent J; ii) diluting the macroaggregated albumin or stannated macroaggregated albumin with water and adding excipients; iii) optionally lyophilizing the reaction mixture of step ii); and i) radiolabeling with X, wherein steps ia) to ig) are carried out as automated continuous process; and wherein the average particle size of the macroaggregated albumin particles is 25 to 35 µm, at least 95% of the macroaggregated albumin particles are between 10 µm to 70 µm, not more than 3% particles are below 10 µm and no particle is larger than 100 µm; and wherein the reconstituted and/or ready-to-use composition has not more than 5% soluble and dispersed radiochemical impurities. Accordingly, the claims are overlapping in scope directed to a lyophilized composition comprising macroaggregated albumin, stannous chloride, saline, albumin, particle size and range and are obvious variants of one another. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 3-7, 10-18 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Schramm et al. (US 6,730,286) in view of Rousso (US 2009/0304582).
The instant claims are directed to a sterile, non-pyrogenic, lyophilized pharmaceutical composition, comprising: i) macroaggregated albumin; ii) stannous chloride; iii) human serum albumin; and sodium chloride; wherein the macroaggregated albumin is stannous incorporated macroaggregated albumin and wherein the average particle size of the macroaggregated albumin particles is 20 um to 35 um when measured by optical microscopy and/or automated microscopy and image analysis; wherein at least 95% of the macroaggregated albumin particles are between 10 um to 70 um, less than 3% of the macroaggregated albumin particles in the lyophilized pharmaceutical composition are below 10 µm and none of the macroaggregated albumin particles are above 100 um when measured by optical microscopy and/or automated microscopy and image analysis; wherein the macroaggregated albumin particles have not more than 3% soluble and dispersed human serum albumin content, when measured by optical microscopy and/or automated microscopy and image analysis; wherein the lyophilized pharmaceutical composition is a single dose or a multiple dose composition: wherein the number of macroaggregated albumin particles in a single dose of the multi-dose lyophilized pharmaceutical composition is within the range of 300,000-700,000 and the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles between two single doses of the multidose lyophilized pharmaceutical composition is about 400,000 particles or less; and wherein the composition has a shelf-life of two years when stored at a temperature of 25°C.
Schramm teaches a process for preparing a sterile, injectable suspension of human serum albumin which is radiolabeled with technetium-99m for use in lung scanning diagnostic procedures and the radiolabeled product prepared by this process (column 3).
The particles of the human serum albumin constituent of the present invention are characterized as macroaggregates which are of irregular shape having an average diameter of between 5 to 100 microns or more.
To form the macroaggregates of the present invention, the purified human serum albumin is first buffered with a suitable buffering agent to a pH of about 4.95 to 5.25, and preferably to the pH of 5.1. Suitable buffering agents are sodium acetate, acetic acid, sodium acid phosphate, disodium phosphate or other art-accepted buffering agents which are readily removable from the final product.
The addition of a stannous salt dissolved in an inorganic acid, such as hydrochloric acid, to the buffered, purified solution of the human serum albumin results in a homogenous mixture of the stannous salt and the purified albumin (column 5).
At the completion of the heating/cooling cycle the macroaggregate suspension is aseptically centrifuged and the supernatant is discarded. The separated macroaggregates are resuspended using sterile water for injection and passed through a sizing screen so that no larger particle size macroaggregates will pass through the sizing screen than desired. We prefer using a 75 micron sterile sizing screen, however, other sizing screens may be used, such as 60 micron size or lower (column 6).
The protein concentration of the sized suspension is determined by assaying the suspension. Based on the protein concentration found, the batch volume is adjusted so that the desired concentration of mg of aggregated albumin per ml of suspension is achieved. We prefer to have a final concentration of denatured aggregates of human serum albumin of 1.5 mg per ml of suspension and 10 mg undenatured albumin per ml of suspension. For adjustment of the concentration, 5% w/v purified albumin is added to the suspension using a 0.2 micron filter and nitrogen purged filter sterilized or sterile water for injection (column 6).
Following the concentration adjusting step 1.0 to 1.5 ml aliquots are aseptically transferred into sterile, pyrogen-free glass vials. Sterile, pyrogen-free, fluted stoppers are placed on the vials and their content is lyophilized to dryness. The vials are then flooded with sterile nitrogen, their stoppers are seated, sealed with aluminum or plastic seals and stored at 2°C to 8°C. Alternatively, the suspension may be stored at 2° to 8°C without lyophilization if the suspension is intended to be used within a short time period.
The lyophilized macroaggregates are reconstituted with a sterile, pyrogen-free solution of sodium pertechnate Tc-99m forming a suspension of Tc-99m radiolabeled macroaggregates of human serum albumin. See also Examples 1-2.
Preferred range of macroaggregates and adjuncts per vial are shown in Table I-II.
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498
420
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The particle size distribution was determined by optical microscopy using a hemocytometer (column 10).
Characteristics of the product obtained by the process are shown in Table IV.
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510
414
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248
396
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Accordingly, a sterile lyophilized composition comprising the claimed components and the claimed average particle size is taught, and reconstituted compositions thereof comprising 99mTc are taught.
With regard to claim 15, Schramm does not specifically recite a single dose composition comprising i) about 0.02 mg macroaggregated albumin; ii) not less than 5 mg of stannous chloride; iii) about 1.0 mg human serum albumin; and iv) about 0.09-0.15 mg sodium chloride.
Rousso teaches methods of radioimaging, such as radioimaging a lung perfusion including comprising administering to a subject less than about 5 mCi Tc99m MAA (paragraph 0177+).
In one embodiment, the container contains a single dose of the radiopharmaceutical agent, which dose is appropriate for use with the imaging protocol information (paragraph 1082).
In some embodiments of the present invention, the information-bearing radiopharmaceutical agent container and/or the patient-specific data carrier is configured to contain protocol information for performing an imaging procedure using the labeled radiopharmaceutical agent (also referred to herein and in the claims as "radiopharmaceutical") held by the container. For some applications, the protocol information includes SPECT imaging protocol information, and the imaging system uses the protocol information to perform a SPECT imaging procedure using the labeled radiopharmaceutical agent contained in the container. For some applications, the agent container contains a single dose of the labeled radiopharmaceutical agent, which dose is appropriate for use with the imaging protocol (paragraph 2376).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a single dose formulation of the MAA compositions taught by Schramm when the teaching of Schramm is taken in view of Rousso. While Schramm teaches a vial comprising 10 doses (see column 5), it would have been obvious to one of ordinary skill in the art at the time of the invention to provide single-dose containers with a reasonable expectation of success, e.g. as a means of convenience; because it is known for use with an imaging protocol as well as providing dosage which is appropriate for use with the imaging protocol. It is noted that the preferred amounts in Schramm’s vial (Table 1) may be divided by 10 doses as in Table V to arrive at amounts with “about” the claimed ranges and maintaining the same ratios. Furthermore the claims differ from the reference by reciting various concentrations of the active ingredient(s). However, the preparation of various pharmaceutical compositions having various amounts of the active agent is within the level of skill of one having ordinary skill in the art at the time of the invention. It has also been held that the mere selection of proportions and ranges is not patentable absent a showing of criticality. See In re Russell, 439 F.2d 1228 169 USPQ 426 (CCPA 1971).
With regard to the limitations of claims 3, 16 and 19 wherein less than 3% of the macroaggregated albumin particles are below 10 um and none of the macroaggregated albumin particles are above 100 um and have not more than 3% soluble and dispersed human serum albumin content or impurity content, when measured by optical microscopy and/or automated microscopy and image analysis, it is noted that 100% particle distribution between 10 and 15 microns and RCP 98.8% are shown in Table V.
With regard to claims 4, 13, 14, 20 and 21, directed to functional recitation such as pH of reconstituted solution wherein the claim is directed to a lyophilized composition; storage and in vivo properties, it is noted that the Office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same functional characteristics of the claimed product. In the absence to the contrary, the burden is upon the applicant to prove that the claimed products are functionally different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 U.S.P.Q.2d 1302, 1303 (PTO Bd. Pat. App. & Int. 1993), Ex parte Gray, 10 USPQ2d 1922, 1923 (PTO Bd. Pat. App. & Int.) and In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977). The physical properties of the composition of the independent claims are met by Schramm. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
With regard to claim 7, the vial is flushed with nitrogen.
With regard to claim 6, the vials are taught to be sterile.
With regard to claim 10, see MPEP 2113. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). See also Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). However, in the context of an infringement analysis, a product-by-process claim is only infringed by a product made by the process recited in the claim. Id. at 1370 ("a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim").
Regarding claims 12 and 22, reconstitution volume includes 1 or 3 mL (Table IV).
Regarding claim 17, 10-15 mCi radioactivity is taught in Table IV, which is within the claimed range of radioactivity based on the conversion between mCi and MBq as 1 mCi = 37 MBq.
With regard to the limitation directed to particle density of 300,000 to 700,000, it is noted that 3 to 10 million particles are taught per vial and each vial may contain 10 doses in Table IV; accordingly the particle density per dosage unit is within the claimed range.
With regard to the limitation wherein the composition has a shelf-life of two years when stored at a temperature of 25°C, it is noted that Schramm teaches that the lyophilized formulation has excellent stability at both 40 C and at room temperature (column 4).
Further, it is taught that the protein concentration, i.e. concentration of macroaggregated albumin was determined and the specific (final batch) volume containing 1.5 mg/ml of the macroaggregated albumin based on the total quantity of macroaggregated albumin present was calculated. Purified human serum albumin was added as a stabilizing agent for the macroaggregates during subsequent lyophilization and to improve shelf storage time (column 9). Accordingly, it would have been obvious to slightly optimize purified HSA content as a result-effective variable as a means of enhancing stability. Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
With regard to the amended limitation wherein the number of macroaggregated albumin particles in a single dose of the multidose lyophilized pharmaceutical composition is within the range of 300,000-700,000 and the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles between two single doses of the multidose lyophilized pharmaceutical composition is about 400,000 particles or less; it is considered that it would have been obvious to one of ordinary skill in the art to minimize the difference between the number of particles in a multidose composition because Schramm teaches that particle size can be made essentially uniform by using a controlled heating-cooling cycle when producing the macroaggregates; and that this enables the control of the number of particles per vial (paragraph 0011). With regard to the number of particles in a single dose vial, it is considered that with regard to claims directed to a single dose vial, the claim is directed to a single vial and comparison to another vial does not distinguish over the contents of the single vial itself.
Response to arguments
Applicant argues that Schramm discloses each vial as containing 3 to 10 million particles per vial with each vial containing 10 doses. As recognized in the Office Action, a single, unit dose would contain 300,000 to 1,000,000 particles. Applicant asserts that the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles in two individual doses of the lyophilized pharmaceutical composition is about 700,000 particles, i.e., the difference between 1,000,000 particles and 300,000 particles.
Applicant asserts that as explained in the declaration previously submitted, the difference between the maximum number of macroaggregated albumin particles and the minimum number of macroaggregated albumin particles in unit doses of the lyophilized pharmaceutical composition is a critical variable that affects the safety and quality of the resulting radiopharmaceutical product. Applicant asserts that as explained at paragraph 6 of the previously submitted Declaration of Vijayaraj Kuniyil Kulangara dated July 3, 2025, the number of particles in a unit dose is one of the most important characteristics for the safe clinical use of a radiolabeled macroaggregated albumin product. One critical requirement in a radioimaging procedure is to provide the minimal amount of radiation in a dose while simultaneously providing the desired imaging thereby avoiding excess radiation exposure to the patient and staff. Applicant further argues that considering the teachings of Gale and Dworkin, if a unit dose of 300,000 radiolabeled particles provides the minimal amount of radiation to provide the desired imaging quantity, then a unit dose of 1,000,000 radiolabeled particles as taught in Schramm would provide significantly more radiation exposure then needed, more than 3 times more radiation. Applicant asserts that the lyophilized pharmaceutical composition of claim 1 has a difference of 400,000 particles or less between individual doses while Schramm discloses a difference of 700,000 particles or less between individual doses, which is a difference of 75% more than the claimed composition. Applicant argues that Rousso fails to cure the deficiency in Schramm wherein the lyophilized pharmaceutical composition has a difference of 400,000 particles or less between individual doses.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that
With regard to the arguments directed to the Declaration wherein the number of particles in a unit dose is one of the most important characteristics for the safe clinical use of a radiolabeled macroaggregated albumin product, it is noted that the data in the specification is not commensurate in scope with the claims. It is noted that data provided in Table V showing a difference of 400,000 particle number between vials is directed to single dose vials, however the claims are directed to multidose vials. Further, with regard to claims directed to a single dose vial, when a claim is directed to a single vial, and comparison to another vial does not distinguish over the contents of the single vial itself. See MPEP 716.02(d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Applicant further argues that second, Schramm does not disclose at least 95% of the macroaggregated albumin particles in the lyophilized pharmaceutical composition to be between 10 µm to 70 µm. The Office Action states that the particle size distribution was determined by optical microscopy using a hemocytometer and references column 10 of Schramm and the data in Table IV, which reports a particle size range of more than 90% between 10 and 90 microns. Contrary to the assertion in the Office Action, Schramm reports the particle size of macroaggregated albumin particles in a solution rather than the particle size of the lyophilized pharmaceutical product. The particle size range of Table IV is necessarily measured in a solution. Applicant asserts that particle counting with a hemocytometer requires the use of a solution of the measured particles.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the Schramm readily teaches that the vials and their content is lyophilized to dryness, see column 6+ and Examples. The instant claims require a lyophilized composition and that the particles have the claimed size distribution when measured by optical microscopy and/or automated microscopy. It is respectfully submitted that Schramm also teaches that the particle size distribution was determined by optical microscopy using a hemocytometer (column 10). Accordingly, Schramm meets the instant claim language such that a composition that has been lyophilized is measured by optical microscopy.
Conclusion
No claims are allowed at this time.
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 LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618