CASE PATOS3689-US-POT
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`IN RE PCT NATIONAL STAGE APPLICATION OF
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`Am Unit 41424142
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`Sigg, Juergen
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`Examiner: SPAMER, DONALD
`ROBERT
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`INTERNATIONAL APPLICATION NO: PCT/EP2010/06001 14
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`FILED: July #3, 2070
`U.S. APPLICATION NO: 13/382380
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`35 USC §371 DATE: January 05, 2072
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`FOR: Surface Decontamination of Prefilecl Containers in Secondary
`Packaging
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`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
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`DECLARATION GF JUERGEN SIGG, Ph.D.
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`1, Juergen Sigg, declare and say that:
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`1.
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`| reside at Karl-Arzet-Weg 25, Loerrach, Germany.
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`2,
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`lam employed by Novartis Pharma AG (“Novartis”), located at Fabrikstrasse, Basel,
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`Switzerland.
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`| have been so employed since 1992. Mytitle is Principal Fellow.
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`{n this position,
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`which } have held since 2006,
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`| am responsible for development, transfer and validation of
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`pharmaceutical
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`formulations
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`and manufacturing
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`processes
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`of
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`biotechnically
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`derived
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`pharmaceutical drug products.
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`3.
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`1
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`received a Ph.D. degree in Pharmaceutical Technology from University of
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`Ragensburg in Regensburg (Germany) in 1991.
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`4.
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`| am the sole inventor of the invention claimed in pending patent apptication, U.S.
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`Serial No. 43/382380, with claims 1-7 and 22 directed to a mathod for surface decontamination
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`of a pre-filled container.
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`NOVITC(US)00905325
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`
`Regeneron Exhibit 1091.001
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`

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`| understand that the PTO Patent Exarniner has rejected claims 7, 4, 5, 7, and 22 as
`5.
`obvious over Metzner ef af, published U.S. Patent Application No. 2003/0003014 (‘Metzner’),
`as evidenced by and in view of Hasegawa et al., U.S. Patent No, 6,228,324 ("Hasegawa") and
`further in view of Dalmasso et al, U.S. Patent No. 5,788,941 ("Daimasso").
`{| have read and
`understand Metzner, Hasegawa and Dalmasso. The Examiner asserts that Metzner teaches
`the claimed method, but that the “method taught by Metzner includes a step of lowering the
`pressure in the treatment chamber below ambient atmospheric pressure prior to the application
`of hydrogen peroxide and subsequent decontamination.” (January 3. 2013 Office Action, page
`9).
`In response to the Applicants’ assertion that the claimed method does not include the step
`of lowering the pressure prior io application of H,.Q., the Exarniner cited Dalmasso for its
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`teaching that “effective sterilization can be achieved at atmospheric (ambient) pressure and
`roomtemperature.” (/d.}. The Examiner concludes that a “person having ordinary skill in the art
`at the time of the invention would have found it obvious to simplify the method taught by
`Metzner by applying the hydrogen peroxide vapor causing subsequent decontamination at
`ambient (atmospheric) pressure ... with a reasonable expectation of success as taught by
`Dalmasso et al.” (d.).
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`6.
`1 believe that the Examiner's conclusion with regard to. Metzneris incorrect. The
`method taught by Metzner wouid ikely result in denaturation of the protein inthe syringe, or 4
`non-sterile pre-filled syringe, or both. More specifically, if the method of Metzner were used,
`i.@., carrying out the sterilization under vacuum, this. would likely cause a breach in the syringe
`seal, which in turn could cause entry of the HO, inte the syringe.. This would cause
`in
`denaturation of the protein in the syringe, which is sensitive to H,O.-facilitated degradation.
`addition, in the vacuum method taught by Metzner, if the syringe in question contained.an air
`bubble (even a very small air bubble), the plunger stopperin the syringe would be pulled back
`by @ certain distance upon application of the vacuum, and would thus cover parts of the inside
`of the syringe barrel, preventing these paris from exposure te the HO, and thus from
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`sterilization. And, subsequent to the sterilization step, when the vacuum is released, the
`plunger would mave back into its original position and. expose this non-sterile surface to the
`environment. Thus the vacuum method taught by Metzner may not result in a sterite product.
`Metzner does not teach any steps that can be taken to avoid breach of the syringe seal or
`movement of the syringe as the vacuum is applied and then removed. One possible solution to
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(US)00905326
`
`Regeneron Exhibit 1091.002
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`these problems resulting from using the method of Metzner would be to use a method such as
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`the claimed method, in which there is ne pressure change during the sterilization process.
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`| believe
`7. The Examiner contends that one such methodis that taught by Dalmasso.
`that the Examiner's conclusion with respect to Dalmasso is incorrect, for the reasons stated
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`below. As a first matter, | would not look to the teachings of Dalmasso for guidance if | were
`seeking a method of sterilizing a primary container, ¢.g., a syringe, containing a protein
`sensitive to H,0.-facilitated degradation, wherein the syringe was itself packaged in a
`secondary containerprior to sterilizing. And, even if] was already aware of the teachings of
`Dalmasso, { do not believe that the teachings cf Dalmosso, taken alone or combined with thase
`of Metzner (or any of the other references cited by the Examinerin this case), could help a
`person of ordinary skill in the art-to arrive at the claimed invention with any expectation of
`success, The methad taught by Dalmasso relates to a completely different technical problern
`than the one addressed by the claimed inverition, Le., sterilization of bone tissue prior to
`transplantation. Dalriasso states that the bone tissue can even be pre-treated with liquid
`hydragen peroxide solution, which gives evidence that bone tissue is not sensitive to HO,
`(column 4, line 42), unlike the protein in the syringe in the claimed invention.
`in addition, the
`method taught by Dalmasso does not use secondary packaging for the bone tissue. te be
`sterilized.
`In fact, Dalmasso teaches that if penetration of the bane beyondits cortical surfaceis
`needed, sterilization under vacuum may be desired, and even then, fat and marrow that fill
`spaces within the bone should be removed te allow the H,O, vapors to enter these spaces.
`(See Dalmasso at column4, lines 3-5). Thus, Dalmasso indicates thai in the absence of a
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`vacuum, only limited penetration into the surface of the bone is achieved, and even then, thatis
`when there js no packaging around the bone.
`In short, contrary to what the Examiner contends,
`it is not a simple, triviel matter ta merely perform the Metzner method at ambient (atmospherit)
`pressure based upon the teachings of Dalrnasso. Put another way, the Metzner arid Dalmasso
`methods could not be cornbined with any expectation of success.
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`8. A person of ordinary skill in fhe art when seeking a method of sterilizing a syringe,
`containing a protein, wherein the syringeis itself packaged in a secondary container, would nol
`lock to the Dalmasso reference for guidance, and certainly would not look to combine non-
`analogous methods,i.e., Metzner and Dalmasso, with any expectation of success.
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`NOVITC(US)00905327
`
`Regeneron Exhibit 1091.003
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`9. With the claimed invention, the syringe, the surface of which is to be sterilized, is
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`sealed in secondary packaging. Conventional thinking, at the time offiling the current patent
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`application, was-ihat in order to get the sterilizing agent to penetrate the packaging, a vacuum
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`would have ta be applied. However, as | state above, that carries with it the risk thal (i) the seal
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`of the syringe is compromised, leading to degradation of the protein product, or (ii) that the
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`plunger is moved during application and removal of the vacuum, leading to. incomplete
`sterilization. The present application disclosed for the first time, and contrary to conventional
`thinking, that it ig possible to obtain sufficient sterilization of the cuter surface ofa, syringe in
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`secondary packaging at ambient pressure.
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`All statements mace herein based on knowledge are true and all statements made
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`herein based on knowledge. and belief are believed to be true. All statements made herein were
`made with the knowledge that wilful false staternents. and the like may jeopardize the
`patentability of the above patent application and the validity of any patent that issues from i,
`and may subject me to penalties, inclucing fines and imprisonment, under Section 1001, Title 18
`of the United States Code.
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`Respectfully submitted,
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`Date: &
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` Juergen Sigg! Ph.D.
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`NOVITC(US)00905328
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`Regeneron Exhibit 1091.004
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