Planet Depos0
`
`We Make It Happen ™
`
`
`
`Transcript of Horst Koller
`
`Date: December 16, 2021
`Case: Regeneron -v- Novartis (PTAB)
`
`Planet Depos
`Phone: 888.433.3767
`Email: transcripts@planetdepos.com
`www.planetdepos.com
`
`WORLDWIDE COURT REPORTING & LITIGATION TECHNOLOGY
`
`Novartis Exhibit 2189.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`
`1 (1 to 4)
`
`1
`
`3
`
` UNITED STATES PATENT AND TRADEMARK O
`
`ICE
`
` APPEARANCES: (BY VIDEOCON ERENCE)
`
`
`
`
`
`GOODWIN PROCTER LLP
`
`Attorneys for Petitioner
`
` 900 N Street NW
`
` Washington, DC 20036
`
`BY: WILLIAM JAMES, ESQ.
`
` ELIZABETH HOLLAND, ESQ.
`
`
`
`
`
`WEIL GOTSHAL & MANGES LLP
`
`Attorneys for Respondent
`
` 767 ifth Avenue
`
` New York, NY 0 53
`
`BY: CHRISTOPHER PEPE, ESQ.
`
` ANISH DESAI, ESQ.
`
`
`
`
`
`
`
`
`
`
`
`2 3 4 5 6 7 8 9
`
`0
`
`2 3 4 5 6 7 8 9
`
`20
`
`2
`
`2 2
`
` __________________________________________
`
` BE ORE THE PATENT TRIAL AND APPEAL BOARD
`
` __________________________________________
`
` REGENERON PHARMACEUTICALS, INC.
`
` Petitioner,
`
` v.
`
` NOVARTIS PHARMA AG,
`
` NOVARTIS TECHNOLOGY LLC,
`
`0
`
` NOVARTIS PHARMACEUTICALS CORPORATION,
`
` Patent Owners.
`
`2 3 4 5 6 7 8 9
`
` __________________________________________
`
` Patent Number:
`
` 9,220,63
`
` __________________________________________
`
` DEPOSITION O HORST KOLLER
`
` Thursday, December 6, 202
`
`
`
`
`
`2 3 4 5 6 7 8 9
`
`20
`
`Reported by:
`
`MARY . BOWMAN, RPR, CRR
`
`2
`
`JOB NO. 4 5628
`
`2
`
`4
`
` INDEX:
`
`WITNESS EXAM BY: PAGE:
`
`H. Koller Mr. James 6
`
` Mr. Pepe 226
`
`
`
` EXHIBIT INDEX:
`
`NUMBER DESCRIPTION PAGE:
`
`Exhibit 00 U.S. Patent 9,220,63
`
`Exhibit 003 Declaration of Horst Koller
`
`2 3 4 5 6 7 8 9
`
`
`
`
`
`
`
`
`
` December 6, 202
`
` 9:00 a.m.
`
`
`
`
`
` Deposition of HORST KOLLER, held at
`
`0
`
`767 ifth Avenue, New York, New York, 0 53, before
`
`0
`
`Exhibit 080 Article entitled 39
`
`Mary . Bowman, a Registered Professional Reporter,
`
` "Intravitreal siliconee Oil
`
`2 2
`
`2 3 4 5 6 7 8 9
`
` Droplets ollowing a Cap Knife
`
` Injection"
`
`Exhibit 007 Sigg application, 46
`
` WO200 /006877 A
`
`Exhibit 029 Lam application, 7
`
` WO2008/077 55A
`
`Exhibit 2022 Article entitled "Syringe 96
`
` Siliconization Process
`
`2 3 4 5 6 7 8 9
`
`20
`
` Investigation and
`
` Optimization"
`
`2
`
`
`
`2 2
`
`Certified Realtime Reporter, and Notary Public of
`
`the State of New Jersey.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2 3 4 5 6 7 8 9
`
`20
`
`2
`
`2 2
`
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`Novartis Exhibit 2189.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`7
`
`8
`
`Transcript of Horst Koller
`Conducted on December 16, 2021
`
`5
`
`2 (5 to 8)
`
` Q. Have you submitted any declarations in
`any matters other than the declaration you
`submitted in the IPR we are here to talk about
`today?
` A. No.
` Q. Are you billing Regeneron as one of
`your consulting clients at HK Consulting?
` A. No.
` Q. So you are billing Regeneron as an
`expert outside of your normal consulting business,
`is that right?
` A. I am billing Weil.
` Q. Sorry. I'll change my question then.
` Are you billing Weil as part of
` HK Consulting?
` A. Yes.
` Q. How many hours have you billed them
`for since your deposition in February?
`Approximately?
` A. Sixty, 70 hours.
` Q. Sixty to 70 hours?
` A. Yeah.
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
` EXHIBIT INDEX:
`
`NUMBER DESCRIPTION PAGE:
`
`Exhibit 04 Article entitled "Guidance
`
`8
`
` for Industry Container Closure
`
` Systems for Packaging Human
`
` Drugs and Biologics"
`
`Exhibit 008 Boulange application 29
`
` WO2009/030976 A
`
`Exhibit 036 Document entitled "Guidance 77
`
`0
`
` for Industry, Sterile Products
`
`2 3 4 5 6 7 8 9
`
` Produced by Aseptic
`
` Processing, Current Good
`
` Manufacturing Practice"
`
`Exhibit 009 Printout from Drugs.com 85
`
` on Macugen
`
`Exhibit 08 Macugen label 99
`
`Exhibit 0 9 20
`
` version of USP 34 N 29 203
`
`Exhibit 0 2 Article "Drug Delivery of 224
`
` Sensitive Biopharmaceuticals
`
`2 3 4 5 6 7 8 9
`
`20
`
` with Prefilled Syringes"
`
`
`
`
`
`2
`
`2 2
`
`6
`
`EXAMINATION BY
`MR. JAMES:
` Q. Good morning. Could you please state
`and spell your name for the record.
` A. Yeah, my name is Horst Koller,
`H-O-R-S-T, K-O-L-L-E-R.
` Q. And could you provide us with your
`address please?
` A. Yes, my address is Weinbergweg, Route
`1 -- do you want me to spell it?
` Q. I think so.
` A. W-E-I-N-B-E-R-G-W-E-G 1 in 730
`U-Z-N-A-C-H, Switzerland.
` Q. And you understand that you are under
`oath this morning, correct?
` A. Correct.
` Q. I took your deposition this past
`February. Do you recall that?
` A. I recall it.
` Q. And have you given any other testimony
`since I took your deposition in February?
` A. No.
`
` Q. Since you -- strike that.
` I think you told me that you had
`been working on the '631 patent matter since 2017,
`right?
` A. Right.
` Q. And how many total hours would you say
`you've worked on this matter since 2017?
` A. Including deposition?
` Q. Yes.
` A. 200. Approximately.
`0
` Q. And what is the total amount of money
`11
`you've billed Weil for this matter since you
`12
`began, approximately?
`13
` A. I stated, it's times 450 per hour. So
`14
`it's like -- I don't recall the amount -- it's
`15
`like if you say 100 hours is 45,000, 200 hours
`16
`would be 90,000. Is that right?
`17
` Q. So 100,000 dollars, something like
`18
`that?
`19
` A. Something like that.
`20
` Q. It's been a long time since I've done
`21
`math.
`22
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`1234567891
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`Novartis Exhibit 2189.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`9
`
`3 (9 to 12)
`
`clients, have you consulted with them on Lucentis?
` MR. PEPE: Objection, same caution.
` A. No.
` Q. What about Ilea?
` MR. PEPE: I will object and give you
` the same caution.
` A. Yes, I had one project involving Ilea.
` Q. Is that completed?
` A. Completed.
` Q. I'm going to mark a couple of
`exhibits. I think we will use the exhibit numbers
`from the IPR if that's OK with everybody. This is
`Regeneron Exhibit 1001 and it's a copy of the '631
`patent.
` (Exhibit 1001, U.S. Patent
` 9,220,631 marked previously for
` identification.)
` Q. And the second exhibit will be the
`declaration of Horst Koller in this IPR Regeneron
`Exhibit 1003.
` (Exhibit 1003, Declaration of
` Horst Koller marked previously for
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
` You said 200 hours total?
` A. Um-hm.
` Q. So 90,000 dollars or something like
`that, right?
` A. Yeah.
` Q. Now, I think you told me last time we
`talked that HK has clients other than Regeneron,
`right?
` A. I don't have Regeneron as a client.
` Q. I'm sorry, in addition to Weil, you
`have other clients, right?
` A. I have other clients, yes.
` Q. For any of those other clients, have
`you offered opinions on the '631 patent?
` A. No.
` Q. What about any foreign counterparts of
`the '631 patent, have you consulted with any of
`your other clients on those?
` A. What do you mean by foreign
`counterparts of the '631?
` Q. So the Novartis patent family that
`resulted in the '631 patent has members that are
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`
` identification.)
`issued in other countries and I was wondering if
` Q. Just take a moment and look through
`you have offered opinions on any of those other
`Exhibit 1003 and confirm that that is, in fact,
`patents to your other consulting clients.
`your declaration.
` MR. PEPE: So Horst, I'm just going
` A. Yes, it is my declaration.
` to object and caution you not to disclose
` Q. Who drafted that?
` any confidential information along with your
` A. I drafted that.
` clients in answering your question. You can
` Q. All of it?
` answer if you can do so without doing that.
` A. I got support from the legal
` A. No, I did not consult any other patent
`department on like commercial -- I was giving a
`issues besides the IPR here.
`0
`layout and then my counsel had me to put it in the
` Q. I think the last time we talked, you
`11
`right form because I'm not a native speaker. They
`mentioned that you had been consulting with a
`12
`are --
`client who was making a biosimilar of a VEGF
`13
` Q. When you say the legal department,
`antagonist. Right?
`14
` A. Right.
`what do you mean by that?
`15
` A. I mean by Weil.
` Q. Is it just one client?
`16
` A. No, multiple clients.
` Q. Weil?
`17
` A. Yeah.
` Q. For any of those clients, have you
`18
`discussed the '631 patent or its foreign
` Q. So they provided the legal parts of
`19
`counterparts with them?
`the declaration, is that right?
`20
` A. No.
` A. Yes, that's right.
`21
` Q. For any of your other HK Consulting
` Q. Did they provide you with prior art?
`22
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`2
`
`Novartis Exhibit 2189.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`3
`
` A. Right.
` Q. You're not a physician?
` A. I'm not a physician.
` Q. You you've never given an intravitreal
`injection, right?
` A. Right.
` Q. You have no experience administering
`intravitreal injections, right?
` A. Right.
` Q. You have no personal experiences with
`the forces that are associated with an
`intravitreal injection, right?
` A. No, not right. I mean, forces should
`be in general level. So -- and I have designed
`syringes with typically low break loose, glide
`forces for general purposes.
` So I was designing prefilled
`syringes with, you know, break loose and glide
`forces for the intended use for application of
`simple biotech products and they require for
`subcutaneous or, you know, low -- suitable low
`gliding forces and break forces.
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
` A. Yes.
` Q. And you searched for some of the prior
`art yourself as well, right?
` A. Right.
` Q. A couple of the references that you
`have relied on are the Sigg and Lam applications.
`Do you recall what those are?
` A. Yes, I recall what those are.
` Q. Did Weil provide those to you?
` A. I -- I don't remember. I mean, I
`started in 2017. I'm not -- I cannot recollect
`exactly which one was given and which one I found
`myself by having to look into prior art
`references.
` Q. And what about the Boulange reference?
` A. Same.
` Q. Were you aware of the Boulange
`reference before 2017?
` A. I was not aware of the Boulange
`reference prior to 2017.
` Q. You were working in the industry but
`you weren't aware of the Boulange reference,
`
`1234567891
`
`4
`
`right?
` A. Right.
` Q. So how much time did you spend
`drafting that declaration?
` A. This declaration, the new one here?
` Q. Yes.
` A. Thirty, 40 hours.
` Q. And that was on top of the time that
`you spent on your earlier declarations that built
`into that, correct?
` A. Yes. On top. Yeah.
` Q. Are there any things in that
`declaration you would like to correct?
` A. No.
` Q. Now, you have the equivalent of a
`master's in engineering from a university in
`Germany, right?
` A. Right.
` Q. You're not a chemist?
` A. I'm not a chemist.
` Q. And you don't hold yourself out as an
`expert in chemistry, right?
`
` Q. But you have no personal experience
`with the actual forces that a doctor feels when
`they give an intravitreal injection, right?
` A. Right, I never gave an intravitreal
`injection myself.
` Q. And you have no personal hands-on
`experience with how differing forces can impact an
`intravitreal injection, right?
` MR. PEPE: Object to form.
` A. I cannot judge that one on
`0
`intravitreal injection. But I have enough
`11
`experience to judge differences in break loose
`12
`gliding force performance independent of the
`13
`intended use.
`14
` Q. But you have no experience, personal
`15
`experience with how the change in forces of an --
`16
`in a syringe can impact an intravitreal injection,
`17
`right?
`18
` MR. PEPE: Object to form.
`19
` A. As I said, I don't have intravitreal
`20
`injection experience. But the systematic behind
`21
`low forces and avoiding shattering or stick slip
`22
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`4 (13 to 16)
`
`5
`
`6
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`Novartis Exhibit 2189.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`7
`effect and having decent glide force is the same
`for other syringe application as well. Not for
`only intravitreal.
` You need to take extra care, as
`it is written in the prior art, to find the right
`spot in doing intravitreal injection. But the
`handling of a systematic approach for break loose
`and glide forces and, therefore, injection is a
`general design feature for development of prefilled
`syringes.
` Q. But the impact of a slip stick effect,
`when giving an intravitreal injection, can have a
`much more deleterious effect on the patient than
`the same effect in a subcutaneous injection,
`right?
` A. It depends on the outcome of that one,
`because if you are using like low volume syringes
`also for injection of hyaluronic acid around the
`eye or around sensitive, you know, areas in your
`body, let's say in your face, then this, of
`course, the stick slip effect has the same also,
`very, you know, let's say effect regarding pain.
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`syringes, right?
` A. Right.
` Q. You didn't do any work related to
`intravitreal injections while you were at Abbott,
`right?
` A. Right.
` Q. And after Abbott, you moved on to a
`company called Schott, right?
` A. Right.
` Q. And what years were you at Schott?
` A. I joined Schott in the year 2000 and
`left Schott in the year 2015.
` Q. While you were at Schott, you used
`ethylene oxide sterilization, right?
` A. Right. Not only.
` Q. But you do have experience at Schott
`using ethylene oxide sterilization?
` A. Right.
` Q. And that was on at least syringes that
`were filled with water, right?
` A. Yes. In addition to that, ethylene
`oxide is used to sterilize the prefilled syringes
`
`5 (17 to 20)
`
`9
`
`20
`
`prior to filling.
` Q. So ethylene oxide is used to sterilize
`the components of a prefilled syringes before they
`are filled, is that right?
` A. The syringe's barrel, right. It might
`be different sterilization for the rubber
`components involved in the aseptic filling
`process.
` Q. And why might it be a different
`process for the rubber components?
`0
` A. That depended on intended use because
`11
`of convenience. If you do gamma irradiation, you
`12
`can sterilize a full pallet load and it is sort of
`13
`like continuous process.
`14
` If you do, as an example, steam
`15
`sterilization or ETO, it's always a batch process.
`16
`And you need have to have different packaging
`17
`available like Tyvek for gas permeation and double
`18
`PE bag for gamma irradiation or E-beam.
`19
` Q. Now, during your time at Schott, you
`20
`didn't use ethylene oxide to sterilize a syringe
`21
`filled with a sensitive biologic, right?
`22
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`1234567891
`
`8
`
` Q. Right. I think we can agree that the
`stick slip effect can have a negative impact on
`injection anywhere in the body, right?
` A. Right.
` Q. And it can have a very deleterious
`effect on a patient's eye, correct?
` A. Correct.
` Q. That's why extreme care is needed when
`giving an intravitreal injection, right?
` A. Right.
` Q. Have you ever discussed with a
`physician the forces that are required for an
`intravitreal injection?
` A. No.
` Q. Now, at one point in your career, you
`worked at Abbott, right?
` A. Right.
` Q. And at Abbott, you worked on HIV and
`hepatitis test kits and pregnancy kits, right?
` A. Right.
` Q. You didn't do any work during your
`time at Abbott on the preparation of prefilled
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`Novartis Exhibit 2189.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`2
`
` A. Right.
` Q. I think you also told me that while
`you were at Schott, you used vaporized hydrogen
`peroxide to sterilize something you called a
`biosafety cabinet, right?
` A. That was during my time at Abbott.
` Q. At Abbott?
` A. Yes.
` Q. OK. What's a biosafety cabinet?
` A. Biosafety cabinet is a device which
`can work sterile, in a sterile environment. But
`it has the features that the worker is safe
`because it sucks in from the outside to the inside
`to have a user safety in combination with sterile
`environment. That's why it is called biosafety
`cabinet.
` Q. While you were at Schott, you did not
`use vaporized hydrogen peroxide to sterilize a
`prefilled syringe, right?
` A. Right.
` Q. Now, none of your other work at Schott
`was directly related to work on syringes that were
`
`22
`
`used for intravitreal injection, right?
` A. I was working on a development of a
`prefilled syringe where the intended use was the
`idea of using that one as an intravitreal
`injection.
` Q. And was that the Ingentle syringes?
` A. That was the Ingentle syringe.
` Q. That was never commercialized for
`intravitreal injection while you were at Schott,
`right?
` A. Right.
` Q. Now, I think you told me last time
`that you couldn't provide me with any documents on
`your R&D work at Schott because it was
`confidential, right?
` A. Right.
` Q. Do you want to look in your
`declaration there, paragraph 72, please.
` In 72, you have a quote that
` refers to the shelf life of the plunger, right?
` A. In 72?
` Q. Yes.
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`6 (21 to 24)
`
`23
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
` A. Yes, from the near mark.
` Q. And do you have experience -- let me
`strike that.
` Do you have experience determining the
`shelf life of devices?
` A. Yes.
` Q. Would you agree devices must exhibit
`some degree of shelf life stability to obtain
`approval, right?
` A. No.
` Q. So devices don't need any shelf life
`stability, is that your testimony?
` A. No, this is how we need to define
`device. If I am a device manufacturer and I have
`a certain functional shelf life, then the pharma
`company needs to prove the shelf life of the drug
`product. This is not the responsibility of a
`device manufacturer.
` And shelf life sometimes mean,
`for PFS manufacturer, I can guarantee a certain
`sterility claim up to a certain point, and then the
`responsibility goes to the pharma company to fill
`24
`the drug substance, do some stability testing and
`then perform some shelf life testing.
` PFS manufacturer usually have
`shelf life testing regarding functional properties
`like the removal of a tip cap, break loose, glide
`force over typically shelf life storage time under
`certain let's say real temperature or accelerated
`aging conditions.
` Q. There was a lot there so I'm going to
`ask you a couple of questions to follow up.
`0
` I think that you mentioned that
`11
`the shelf life issue could be sort of divided up
`12
`between the syringe manufacturer and the
`13
`pharmaceutical company that puts the drug into the
`14
`syringe, is that right?
`15
` A. That's right.
`16
` Q. And the total container closure system
`17
`with the drug in it, you would agree that has to
`18
`have some sort of shelf life in order to be
`19
`approved by a regulatory agency, right?
`20
` A. The shelf life which the pharma
`21
`company will claim is then not what the company
`22
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`Novartis Exhibit 2189.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`25
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`will approve.
` So if you claim two years but
`only can show data on one year, you don't get
`approved for two years from like the FDA.
` If you have shelf life data for
`three year, but you still want to do two years,
`then you get approval for two years. It's always
`what you claim you need to show facts and data for
`shelf life.
` Q. So you have to show some sort of shelf
`life in order to get approval, but the length of
`the shelf life can vary depending on what the
`company can prove in terms of stability over time,
`right?
` A. Right.
` Q. And I think you mentioned two
`different kinds of stability. One was sterility
`and the other was functional, right?
` A. Sterility is not a -- a claim of shelf
`life. Sterility is sterility. This is defined,
`as you say if I have a sterile system, it needs to
`keep sterility over shelf life. Independent of if
`
`7 (25 to 28)
`
`27
`
`treatment to what I have done to my system.
` So the shelf life is not only one
`claim. It's a combination of functional quality
`and then the drug stability quality and then the
`sterility behind it.
` Q. OK.
` The sterility part of it, if you have
`a shelf life claim for your device of, for
`example, two years, I think what you are saying is
`your device has to be sterile for two years,
`right?
` A. Right, this is the claim. As a
`syringe manufacturer, my claim is two-year
`sterility. Within two years, the pharma company
`should use it and fill it.
` Q. Right, OK. And I think you mentioned
`that for functional stability, break loose and
`glide force would be something that you would have
`to show over time, right?
` A. Yeah, under certain combination which
`is either used in-house as my standard rubber
`component or if you want to offer different
`
`28
`possibilities that you say, OK, I want to check on
`it's like one month or three years shelf life. So
`different rubber formulation or component, then
`sterility is a fixed claim.
`this is a typical usage of a system that you check
` Shelf life, unless if I say it's like I
`on break loose, glide force, particle content.
`have a functional shelf life where the device
` Also you try -- you make
`manufacturer knows that my system is capable of
`sterility testing that you know that your system is
`surviving three-year functional shelf life because I
`tight. This is part of the testing for
`know I can remove my tip cap, I know my rubber is
`functionality of syringes.
`tight. I have decent break-away and glide forces.
` Q. And it's part of the testing of
`This is designed and this is what I write and this
`functionality of syringes over time because the
`0
`is usually what I will tell as a device manufacturer
`regulatory agency is interested in the fact that
`11
`listed also like in the FDA in the so-called drug
`your device can perform the same way over time for
`12
`master file. This is where I put all my information
`the entire shelf life, right?
`13
`about the technical stuff into the system.
` A. Yes. The pharma company filling the
`14
` Then if a pharma company is interested
`drug product needs to be able to show the
`15
`in that system, sterility is a lot of work, of
`functionality to the end their claimed shelf life.
`16
`course, in order to verify that their specific drug
`That whatever the PFS manufacturer is doing
`17
`product can be used within the container closure
`before, this needs to be sort of, of course,
`18
`system.
`verified.
`19
` This is a different issue. They
` I can give certain input and I
`20
`might have something in it which does not allow me
`can say what our typical performance is.
`21
`that I can basically remove my tip cap or I might
` Q. OK, in the real world, let's call it,
`22
`have different forces because they do a different
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`1234567891
`
`26
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`Novartis Exhibit 2189.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`29
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`after the syringe manufacturer provides the
`syringe to the pharma company who then fills it or
`has it filled and now you have a product that has
`a shelf life claim on it, how does that stability
`over time get assessed?
` A. So it depends on the specification of
`your specific drug product. So if you would use
`as an example WFI, which is not officially a drug
`product, but very difficult product to fill and
`keep safe, you say the quality which I put into my
`syringe that's available for all the drug products
`should be the same or maybe only maybe have a
`minimized effect after two or three years at the
`end of shelf life.
` So it's if a water injection, I will
`check on conductivity, on pH, whatever -- in this
`water quality which goes into the -- we say water
`quality and end of shelf life.
` For typical drug products,
`potency effect, if they have a certain potency or
`if they have a certain cleanliness, then this is
`what you know when you put it in, basically
`
`8 (29 to 32)
`
`3
`
`shelf life, let's say, how is that assessed?
` A. So you know that you have a sterile
`product in the first place which are filled into
`the syringes, and then at certain time points,
`what you usually do like every three months or
`every six months depending on your test scheme,
`you take out samples. And one claim for it
`standard USP 71 sterility test where you check, if
`I see bioburden inside, because that would mean
`that I had a container closure integrity breach.
` Q. When you test that bioburden, do you
`compare it to a sterility assurance level?
` A. No. A sterility assurance level is
`given by the sterilization of the system, by a
`so-called media verified that your aseptic filling
`process is done, performed in such a way, and then
`you check and the sterility testing is that you
`don't have any bioburden ingress or that you don't
`show any bioburden, living organism in your drug
`product.
` Q. So the sterility assurance level is a
`validated level that you've demonstrated your
`
`30
`cleanliness -- or I mean potency would be and then
`process can achieve, is that right?
` A. This is -- a sterility assurance level
`at the end of the one, two, three-year shelf life,
`is used during the validation of my sterilization
`you need to show that the potency is still the
`process to show minimum of 10 minus 6 log
`same. This is standard sort of stability claim
`reduction. This is a validated process.
`over shelf life.
` Q. So if you do a single test on a device
` Q. With respect to functional stability,
`and you get a certain result, you can't say
`you would have to demonstrate the same thing,
`whether or not the process met a certain sterility
`right; that over time, your syringe had the
`assurance level, right?
`appropriate function, I think you mentioned that
` MR. PEPE: Object to form.
`the tip cap would come off in a certain way, and
`0
` A. Sterility is only checking on
`also that your break loose and glide forces didn't
`11
`bioburden, independent on what the validation was
`change over time, right?
`12
`doing for your process.
` A. This is complete. One is the
`13
`functional issue and one the drug stability issue.
` Q. OK. The sterility assurance level is
`14
`a validation of your process, is that right? Do I
` Q. Do you know what the shelf lives are
`15
`have that right?
`for the commercially available VEGF antagonist
`16
` A. It's a validation of the sterilization
`prefilled syringes?
`17
`process, yeah.
` A. I don't know.
`18
` Q. And whereas an individual test is
` Q. One last question on that. We talked
`19
`simply a measure of the bioburden of that
`about functionality stability over time, but with
`20
`particular device, whether it has decreased and
`respect to maintaining sterility over time, to
`21
`how much, is that right?
`demonstrate that your product is living up to its
`22
`PLANET DEPOS
`888.433.3767 | WWW.PLANETDEPOS.COM
`
`1234567891
`
`32
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
`Novartis Exhibit 2189.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Transcript of Horst Koller
`Conducted on December 16, 2021
`33
`
`1234567891
`
`0
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`
` A. Right.
` Q. So just staying with the sterility
`assurance level for a moment, you mentioned that
`it's a validated level or value. Can you tell me
`how it's -- how the validation is achieved?
` A. Yeah.
` So sterility is claimed by the
`sterility assurance level, SAL, and sterility is
`defined as having a bioburden reduction of like a 6
`log, reduction so 10 minus 6.
` How it's done is I have certain
`so-called bio indicators which have a certain load,
`known and specific for the sterilization specific
`bioburden, and then I need to show that my
`sterilization kills enough microorganism to
`guarantee the 6 log reduction. Like survival of
`one out of one million, that would be a typical
`value for 6 log reduction.
` Q. So the sterility assurance level is a
`probabilistic value in that you can assert that
`your process will result in a product that would
`only have say one in a million chance of a
`
`9 (33 to 36)
`
`35
`
`3rd, let's say, can you make a sterility claim?
` A. Sterility is usually claimed to 10 to
`the minus 3 -- 10 to the minus 6, excuse me. But
`if you can show 10 to the minus 3 and you still
`show sterility in the end and you can show that
`your overall load of bioburden is not going above
`this, you know, 3 log, then, you know, this is
`usually called also like surface decontamination,
`outside contamination.
` So sterility would always be claimed,
`based on my knowledge, what I have seen on their
`validations I did was always 10 to the minus 6.
` Q. So if you had 10 to the minus 3, you
`could call it, as you said, something like surface
`decontamination or outside decontamination, is
`that right?
` A. You can prove a certain log reduction
`which helps to minimize apparent ingress into the
`product. But it would not usually show a
`sterility claim because the industry expectation
`is, notice from the agencies that is a 10 to minus
`6 log reduction.
`
`36
` Q. Have you seen examples where companies
`nonsterile product, is that right?
`have made a claim that their product is sterile
` A. That is right that you say from 1
`where the SAL is something less than 10 to the
`million to 1.
`minus 6?
` What you usually is that you have
` A. No, I don't have seen information. If
`a higher bioburden load so you can, you know, at
`they claim sterile, for me, that's usually 10 to
`least get to the 10 minus 6 log reduction and that
`the minus 6.
`then guarantees you that you have a sterile
` Q. You keep saying usually. Just why do
`product.
`you use the word "usually"?
` What you then need to s