Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 1 of 27 PageID #: 14255
`
`
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`IMPOSSIBLE FOODS INC.,
`
`Plaintiff,
`
`v.
`
`MOTIF FOODWORKS, INC.,
`
`and
`
`GINKGO BIOWORKS, INC.,
`
`Defendants.
`
`
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`C.A. No. 22-311 (WCB)
`
`
`
`
`
`
`
`SUPPLEMENTAL DECLARATION OF DR. CARL BATT
`
`IN SUPPORT OF MOTIF’S SUR-REPLY CLAIM CONSTRUCTION BRIEF
`
`
`
`
`
`
`
`
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 2 of 27 PageID #: 14256
`
`I, Dr. Carl Batt, declare as follows:
`
`1.
`
`On June 28, 2023, I submitted a Declaration (“Decl.”) in support of Motif’s
`
`Answering Claim Construction Brief in this Litigation. I incorporate that Declaration, including
`
`my opinions therein, herein by reference. My opinions and analysis in my Declaration are
`
`unchanged. I also incorporate my curriculum vitae (Decl. Ex. B1) herein by reference.
`
`I.
`
`SCOPE OF SUPPLEMENTAL ASSIGNMENT
`
`2.
`
`I have been asked to supplement my opinions and analysis provided in my
`
`Declaration in response to positions taken by Plaintiff Impossible Foods and its experts in Reply
`
`claim construction briefing.
`
`3.
`
`I have reviewed Impossible’s Reply Claim Construction Brief regarding the Animal
`
`Terms, the Mxr1 Terms, and “promoter element.” I disagree with Impossible’s positions in this
`
`brief as I explain further below.
`
`4.
`
`I understand that Impossible’s expert, Dr. Paul Sarnoski, submitted a declaration in
`
`this Litigation on July 7, 2023 in support of Impossible’s Reply Claim Construction Brief. In this
`
`declaration (“Sarnoski Decl.”), I see that Dr. Sarnoski has responded to some of my statements
`
`and opinions in my Declaration regarding the Animal Terms. I have reviewed the Sarnoski
`
`Declaration and the exhibits Dr. Sarnoski has cited in support. I disagree with Dr. Sarnoski and
`
`respond to his positions below.
`
`5.
`
`I also understand that Impossible’s expert, Dr. Hal Alper, submitted a declaration
`
`in this Litigation on July 7, 2023 in support of Impossible’s Reply Claim Construction Brief. In
`
`this declaration (“Alper Rep.”), I see that Dr. Alper has responded to some of my statements and
`
`opinions in my Declaration regarding the Mxr1 Terms and “promoter element.” I have reviewed
`
`
`
`2
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 3 of 27 PageID #: 14257
`
`the Alper Reply and the exhibits Dr. Alper has cited in support. I disagree with Dr. Alper and
`
`respond to his positions below.
`
`6.
`
`I reserve the right to further respond to opinions or positions taken by Plaintiff
`
`Impossible, Dr. Sarnoski, Dr. Alper, or other experts of Impossible in due course as this Litigation
`
`proceeds, or to amend or further supplement my opinions herein or in my Declaration as new
`
`information comes to my attention.
`
`II.
`
`REBUTTAL OPINIONS
`
`A.
`
`7.
`
`Supplemental Opinions Regarding Animal Terms
`
`I have reviewed the Sarnoski Declaration with respect to the “Animal Terms.” As
`
`a preliminary matter, it is not clear to me that Dr. Sarnoski is a POSA for the Foodstuff Patents
`
`according to his own definition. Dr. Sarnoski opines that a “POSA would have at least a graduate
`
`degree in food science, biology, chemistry, or a similar discipline, plus 2 years of experience as a
`
`food scientist.” Sarnoski Decl. ¶19. Dr. Sarnoski states that he obtained his Ph.D. in 2010. I
`
`observe Dr. Sarnoski applies a priority date of July 12, 2011 for the ’761 patent and January 11,
`
`2013 for the other Foodstuff Patents.1 Accordingly, from his own admissions, it is not apparent
`
`that Dr. Sarnoski had 2 years of experience as a food scientist after receiving his graduate degree
`
`at the time of the ’761 patent’s priority date.
`
`8.
`
`I disagree with paragraphs 79, 82-83, and 88 of the Sarnoski Declaration for reasons
`
`previously explained in my Declaration. As I previously opined, whether a food or a food
`
`ingredient is “animal” is a function of its genetic origins regardless of what host is used to produce
`
`it, as in the case with a recombinant host. Decl. §IX.A.1. E.g., the patents teach that a non-animal
`
`
`1 I understand from Motif’s Answering Claim Construction Brief that Impossible has
`contended that all Foodstuff Patents are related. I am not aware, and Dr. Sarnoski does not explain,
`why he applies different priority dates for different Foodstuff Patents.
`
`
`
`3
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 4 of 27 PageID #: 14258
`
`“source” is one way to produce animal proteins. Decl. ¶58. The patents thus distinguish between
`
`the protein’s identity and host used to produce it. The claims do not recite the latter concept. Decl.
`
`§§VI.C, IX.B. Dr. Sarnoski apparently disagrees with me but never provides any factual or
`
`evidentiary contradiction to my position that genetic identity dictates whether a protein is
`
`“animal.” Instead, although he does not say so directly, he apparently believes that the proteins’
`
`source dictates whether they are “animal” or not, within the meaning of the Foodstuff Patent
`
`claims. I disagree as explained above.
`
`9.
`
`Dr. Sarnoski discusses certain dependent claims in paragraph 80-81. To the extent
`
`certain claims exclude “animal” proteins or “animal” products, I disagree with Dr. Sarnoski that
`
`these terms are consistent with the independent claims. Myoglobin is well-known to be an animal
`
`protein, as I previously explained. Decl. ¶120. Even Impossible’s cited support recognizes this
`
`fact. See, e.g., Reply Brief Exhibit 14, IF_0014526 (“Myoglobin is a 17.8-kD protein that is found
`
`exclusively in skeletal muscle …. Myoglobin (Mb) is a heme-containing globular protein that is
`
`found in abundance in myocyte cells of heart and skeletal muscle.”); IF_0014529 (“Myoglobin is
`
`an oxygen-binding protein located primarily in muscles.”); IF_0014530 (“Myoglobin is a low
`
`molecular weight oxygen binding heme protein that is found exclusively in heart and skeletal
`
`muscle cells.”). Dr. Sarnoski does not opine that myoglobin is not an animal protein.2
`
`10.
`
`I further disagree with Dr. Sarnoski’s opinions in paragraphs 80-81. I see, for
`
`example, that the sequences highlighted by Dr. Sarnoski (SEQ ID NOS. 18-20) are among a total
`
`
`2 To the extent the patents discuss “myoglobins” from other species, it is unclear whether
`the patents mean myoglobin specifically or rather a “myoglobin-like” protein. Dr. Sarnoski offers
`no opinion on this point. Impossible’s cited support confirms that “myoglobin-like” proteins are
`found in non-animal organisms (“taxa” such as bacteria). Reply Brief page 2, Exhibit 14 (“Mb
`and Mb-like proteins are also found in many taxa, including bacteria, plants, fungi, and animals.”).
`It is not clear to me whether Impossible or Dr. Sarnoski are opining that “myoglobin” includes
`proteins encoded in non-animal species. Regardless, my opinions relating to the significance of
`
`
`
`4
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 5 of 27 PageID #: 14259
`
`of 26 different sequences recited in the claims at issue. Sarnoski Decl. ¶¶80-81. Their inclusion
`
`in the dependent claims is suggestive of an error by the patent Examiner in failing to appreciate
`
`the internal inconsistency between the independent and dependent claims. For example, the
`
`Examiner may have overlooked SEQ ID NOS. 18-20 among the SEQ ID NOS. 1-26 recited in the
`
`dependent claims when allowing the claims.
`
`11.
`
`As I explained in my Declaration, for example, the Examiner deleted “myoglobin”
`
`from a dependent claim in amending the respective independent claim to recite “non-animal”
`
`heme-containing protein. Decl. ¶¶60, 120. Dr. Sarnoski addresses my positions regarding this
`
`amendment. Sarnoski Decl. ¶90. I disagree with his characterization. He states, e.g., that he
`
`“would not understand such an [clarifying] amendment to change the substantive meaning of the
`
`claim.” Id. He does not further explain or identify any basis for his understanding. Nor is it
`
`apparent what expertise Dr. Sarnoski has that qualifies him to opine on whether a claim amendment
`
`is substantive or not, e.g., training in patent prosecution. Regardless, I disagree with Dr. Sarnoski.
`
`The evidence shows that the ’306 patent Examiner recognized that these terms are internally
`
`inconsistent with each other. In my view, failure to make similar amendments in other patent
`
`claims reflects an error by those patents’ Examiners.
`
`12.
`
`I disagree with Dr. Sarnoski’s opinions regarding FDA Standards of Identity.
`
`Sarnoski Decl. ¶¶84-85. I previously explained, for example, that products such as milk (or butter
`
`or cheese) could be “animal products” without changing the meaning of “animal,” a term which
`
`relates to identity. Decl. ¶123. Dr. Sarnoski’s opinions do not address my explanation. Instead,
`
`
`amendments of the claim term “myoglobin” are unchanged in light of the undisputed and abundant
`disclosure that myoglobin is an animal muscle protein.
`
`
`
`5
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 6 of 27 PageID #: 14260
`
`he contrasts animal-sourced milk with plant-sourced “milk alternatives.” I disagree with the
`
`relevance of Dr. Sarnoski’s analysis as explained below.
`
`13.
`
`I have reviewed Exhibit C to Dr. Sarnoski’s declaration, an FDA Guidance
`
`document titled “Labeling of Plant-Based Milk Alternatives and Voluntary Nutrient Statements:
`
`Guidance for Industry.” Exhibit C is dated February 2023 and therefore post-dates the Foodstuff
`
`Patents’ priority date(s) by a decade or more. The relevance of Exhibit C to Dr. Sarnoski’s
`
`opinions is therefore unclear. Exhibit C explains how a producer may label plant-based milk
`
`alternatives below. See Ex. C page 5 (emphasis added). I note that Exhibit C does not state that
`
`these milk alternatives can be produced by recombinant technology and most addresses soy milk
`
`and other extracts from plants.
`
`Plant-based milk alternatives are made from liquid-based extracts of plant
`materials, such as tree nuts (e.g., almond, walnuts, macadamia), legumes (e.g.,
`soybean), seeds (e.g., hemp, flax), or grains (e.g., rice, oat).
`
`
`
`14.
`
`I am not certain what argument Dr. Sarnoski is advancing with respect to the milk-
`
`alternative SOI. Dr. Sarnoski’s comparison does not appear to be relevant to my opinions,
`
`however. In Dr. Sarnoski’s comparison, the two sets of products (animal milk and plant “milk
`
`alternative”) are materials produced by different sources (animals and plants), but these sources
`
`are the native sources of the respective products. My opinions relate to the question of whether,
`
`properly construed, a protein encoded in an animal genome is “animal” or “non-animal” within
`
`the meaning of the Foodstuff Patents’ claims when that protein is expressed in a non-animal source
`
`that does not naturally produce that protein. E.g., Decl. §IX.A.1. Dr. Sarnoski’s milk-alternative
`
`example does not address this question.3 Milk is not just a mixture of specific proteins, lipids,
`
`
`3 Also, milk is not just a mixture of specific proteins, lipids, sugars and other molecules.
`The U.S. Food and Drug Administration (FDA) defines milk as the lacteal secretion obtained from
`one or more healthy cows. The definition includes milk obtained by manual milking or by the use
`
`
`
`6
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 7 of 27 PageID #: 14261
`
`sugars and other molecules. The U.S. Food and Drug Administration (FDA) defines “milk” as the
`
`lacteal secretion obtained from one or more healthy cows. The definition includes milk obtained
`
`by manual milking or by the use of mechanical means from cows that are in good health and are
`
`not under any treatment that could affect the milk’s safety. Taken in total, the process by which
`
`an animal produces “milk” and how it is collected is part of the definition of milk. Dr. Sarnoski
`
`does not offer any evidence (extrinsic or otherwise) to argue that recombinant production of a milk
`
`protein (e.g., casein) naturally encoded and expressed in animal cells should be considered a “non-
`
`animal” protein. It is unclear that any such evidence, even if available, would be relevant to the
`
`meaning of the claimed “animal” or “non-animal” terms given the 2011-2013 priority date Dr.
`
`Sarnoski applies and I disagree with Dr. Sarnoski to the extent he opines that the subject matter of
`
`paragraphs 84-85 are relevant. The analogy has no merit because milk is not a single protein, and
`
`plant-based milks will never be considered to be the equivalent of milk, i.e., lacteal secretion
`
`obtained from one or more healthy cows. The FDA may allow producers of plant-based milk
`
`alternatives to use the word ‘milk’ on their label but modified to reflect its origin (soy, cashew,
`
`etc.) with the added requirement of a comparative nutrition label to inform the consumer of the
`
`differences between the plant-based milk and milk. Further and in support of Motif’s claim that
`
`the origin matters, soy milk must be labeled ‘soy’ to alert consumers who might be allergic to soy
`
`proteins. I reserve all rights to respond to any further opinions he or another expert may offer on
`
`this subject.
`
`15.
`
`Dr. Sarnoski states that Motif uses the term “plant based” to describe Motif’s
`
`products. Sarnoski Decl. ¶86. He cites only to a two-page print-out from a website that bears the
`
`
`of mechanical means from cows that are in good health and are not under any treatment that could
`affect the milk’s safety. Taken in total the process by which an animal produces ‘milk’ is part of
`the definition of milk.
`
`
`
`7
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 8 of 27 PageID #: 14262
`
`URL https://www.nsf.org/food-beverage/food-beverage-product-certification/plant-based-certification.
`
`See Sarnoski Decl. Ex. D. NSF is formerly known as National Sanitation Foundation, a private
`
`entity that, among other things, certifies various equipment and practices in the food industry.
`
`Their self-initiated ‘certificate’ is not sanctioned by any Federal agency and represents a
`
`certification that some individuals may choose to obtain from NSF for a fee. It is not to be confused
`
`with the National Science Foundation, also known (and more widely) as NSF. As with any private-
`
`party certification, the authority and value is in eyes of the beholder. The only date associated
`
`with Exhibit D is “7/7/23”—at least a decade or more after the priority dates applied by Dr.
`
`Sarnoski. I am not certain what argument Dr. Sarnoski is advancing with respect to this term. For
`
`example, it is not clear how “animal-derived” as used in Exhibit D is relevant to any claim term.
`
`Indeed, Dr. Sarnoski states that he “[is] unsure whether Motif is certified” by the NSF
`
`organization. There is no obvious rationale for probing if Motif has this certification, nor the
`
`value to Motif or any organization to having this certification as it relates to the matter at hand.
`
`Therefore, the relevance of Exhibit D to Dr. Sarnoski’s opinions on terms with a 2011-2013
`
`priority date is wholly unclear to me and I disagree with Dr. Sarnoski to the extent he opines that
`
`the subject matter of paragraph 86 is relevant. I reserve all rights to respond to any further opinions
`
`he or another expert may offer on this subject.
`
`16.
`
`Dr. Sarnoski states that “the papers cited by Dr. Batt [in my Declaration] do not tell
`
`a food scientist how the term “non-animal” should be interpreted in the context of the patents.”
`
`Sarnoski Decl. ¶87. I disagree. Dr. Sarnoski cites no support for this statement and it appears to
`
`be entirely conclusory. Nor does Dr. Sarnoski identify any specific statement or analysis from my
`
`Declaration that he disagrees with. I note that Dr. Sarnoski’s experience with recombinant
`
`technology, including in production of foodstuffs or proteins—if any—is not apparent from his
`
`
`
`8
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 9 of 27 PageID #: 14263
`
`identified qualifications. In addition a POSITA would seek to be informed about the term ‘non-
`
`animal’ from a broader sense than just its context in these patents and more than likely seek
`
`guidance from FDA documentation. That documentation makes it clear that the origins of the
`
`protein with regard to where the original gene came from is of utmost importance.
`
`17.
`
`Dr. Sarnoski states that “Dr. Batt and Motif are looking to outside sources and
`
`ignoring the focus and language of the patents.” Sarnoski Decl. ¶87. I disagree. I considered the
`
`Foodstuff Patents and their intrinsic record as explained in my Declaration. E.g., Decl. §§VII,
`
`IX.B.
`
`18.
`
`Dr. Sarnoski quotes twice from a response by Impossible to the Patent Office during
`
`prosecution of the ’241 patent. I am not certain what argument Dr. Sarnoski is advancing with
`
`respect to these statements. To the extent Dr. Sarnoski suggests they contradict my opinions, I
`
`disagree. For example, I see no statements in Exhibit 18 that address the question of whether a
`
`protein genetically encoded in an animal, and therefore “animal” in identity, becomes “non-
`
`animal” when it is synthesized in a non-animal source.
`
`19.
`
`Indeed, Exhibit 18 refers to heme-proteins that are encoded by the same host that
`
`the native genes are expressed in. I excerpt the relevant portion of Impossible’s Exhibit 18 below
`
`(IF_0013133), with highlighting to indicate the proper context of the excerpt quoted by Dr.
`
`Sarnoski. Specifically, I see from my review of Exhibit 18 that the “Hsieh” prior art reference
`
`contained beef. Therefore, the heme-protein in Hsieh was both genetically encoded in beef and
`
`also synthesized in beef. I see that the Examiner argued it would be obvious to combine Hsieh
`
`with another reference, Proulx. As I understand from ’241 patent prosecution, the Examiner cited
`
`Proulx for its teaching of leghemoglobin, a protein whose gene is found in a plant (i.e., soybean)
`
`and can be isolated from it. Ex. B25 (U.S. Application No. 15/913,090, Non-Final Rejection dated
`
`
`
`9
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 10 of 27 PageID #: 14264
`
`May 12, 2020, page 5 (citing “Proulx et al. (“Iron Bioavailability of Hemoglobin from Soy Root
`
`Nodules Using a Caco-2 Cell Culture Model”)), page 7 (“Proulx et al. teach leghemoglobin is a
`
`heme protein identified in soybean root nodules … Proulx et al. disclose a purified leghemoglobin
`
`protein … Proulx et al. teach that the bioavailability of leghemoglobin from soy root nodules is
`
`similar to that of heme iron from animal sources....”) (emphasis altered). With this context, it is
`
`clear to me that when Impossible was referring to “heme from a non-animal source,” Impossible
`
`was referring back to Proulx’s plant-sourced plant protein leghemoglobin. When the portion
`
`quoted by Dr. Sarnoski is considered in context, it says nothing about recombinant production or
`
`genetically modified yeast. In fact, Impossible originally sought to use leghemoglobin from
`
`soybean nodules but then opted to express soy leghemoglobin in a genetically modified yeast,
`
`retaining ‘soy’ as the descriptor for the ingredient to reflect its origins I therefore disagree with
`
`Dr. Sarnoski’s characterization of Exhibit 18.
`
`
`I also observe that Impossible points to Motif’s GRAS notice dated April 15, 2021
`
`
`
`20.
`
`(Reply Brief pages 1-2) in support of certain arguments concerning the Animal Terms. Dr.
`
`Sarnoski does not mention this GRAS notice and Impossible’s brief does not rely on an opinion
`
`by him on this point. In my opinion, as explained above regarding the “milk alternative” and
`
`
`
`10
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 11 of 27 PageID #: 14265
`
`“NSF” evidence cited by Dr. Sarnoski, the 2021 GRAS notice is irrelevant to how a POSITA
`
`would have understood the claims of the Foodstuff Patent roughly 10 years earlier.
`
`21.
`
`However, it is also my opinion that if the GRAS notice is relevant, Impossible is
`
`wrong about the significance of bovine myoglobin’s allergenicity reported in therein. As the
`
`GRAS notice explains, “[t]he myoglobin present in Motif FoodWorks’ Myoglobin Preparation is
`
`100% identical to bovine myoglobin.” Reply Brief Ex. 12 at 25. In addressing potential
`
`allergenicity, for example, the notice discusses the protein’s “amino acid sequence homology”
`
`across “different animal species” in relation to whether the protein is an allergen. D.I. 142, Ex. 12
`
`at 23. In a different disclosure of allergenicity, Impossible (through its attorneys only) argues that
`
`the yeast production system causes Motif’s protein to lack the -Gal carbohydrate (-Gal)
`
`sometimes associated with meat allergies. I disagree with this argument to the extent Impossible
`
`argues the myoglobin is thereby rendered “non-animal.” The -Gal carbohydrate is a post-
`
`translational modification to the myoglobin protein. Thus, the protein’s fundamental genetic
`
`identity as an animal (e.g., bovine) myoglobin is unchanged.
`
`B.
`
`Supplemental Opinions Regarding Mxr1 Terms
`
`(a)
`
`The Term “Mxr1 Transcriptional Activator Sequence” Refers
`to the Coding Nucleic Acid, Not the Binding Site
`
`22.
`
`The patents never use the term “sequence” to refer to a location where Mxr1 binds.
`
`At most, the patents refer to the AOX1 promoter as the region where Mxr1 binds. ’492 patent
`
`39:23-31. But they do not call the binding site itself a “sequence.” This is consistent with how a
`
`POSITA would describe a binding site—i.e., a POSITA would call that region a “binding site.”
`
`In contrast, a POSITA would use “sequence” to describe the nucleic acid sequence that encodes
`
`the Mxr1 transcriptional activator itself or in general any nucleic acid sequence modified by a
`
`
`
`11
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 12 of 27 PageID #: 14266
`
`description of the origins of that sequence, i.e., soy leghemoglobin sequence. This is depicted in
`
`the illustration below:
`
`
`
`23.
`
`Further, I disagree with Dr. Alper’s reading of claim 14 in paragraph 6. The patents
`
`describe an embodiment in which Mxr1 transcriptional activator sequence, as used in that claim,
`
`refers to the protein that is encoded in the nucleic acid sequence rather than a binding site to which
`
`Mxr1 binds. ’492 patent, 4:18-22.
`
`24.
`
`I disagree with Alper Reply paragraph 7. He claims I should not be using the ’656
`
`patent claims as instructive in interpreting the ’492 patent claims. It is unclear what Dr. Alper
`
`means by “the nomenclature between [the patents] is not strictly uniform.” Even if the patents’
`
`claims have some differences in phrasing, the relevant term at issue—the four words Mxr1
`
`transcriptional activator sequence—are the same. This terminology, used in two different claim
`
`sets, arises from the same specification and should have the same meaning in both claim sets. Dr.
`
`Alper does not identify any support in any of the patents where this term—Mxr1 transcriptional
`
`activator sequence—refers to a binding site. The plain and simple meaning of Mxr1
`
`transcriptional activator sequence is the sequence that codes for the Mxr1 activator. The plain
`
`and simple means to designate the region where Mxr1 binds would be the Mxr1 binding site.
`
`
`
`12
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 13 of 27 PageID #: 14267
`
`“Sequence” conveys a degree of certainty with respect to the nucleic acid sequence while in fact
`
`the six Mxr1 binding sites in the AOX1 promoter have very little similarity outside of a 4
`
`nucleotide sequence CYCC (where Y is either a C or a T, ie CCCC)
`
`25.
`
`I disagree with Alper Reply paragraph 8 because his comparison fails to account
`
`for the claims’ actual language. He compares the two terms he emphasizes red, but these terms
`
`are different. Instead, Dr. Alper should have compared the red language in claim 14 with the
`
`language I highlight in claim 26 below.
`
`
`I disagree with Alper Reply paragraph 9 because none of Dr. Alper’s cited support
`
`
`
`26.
`
`uses the term at issue—Mxr1 transcriptional activator sequence. In fact, his cited disclosure
`
`supports my opinion that the patents describe binding sites with different terminology, specifically,
`
`“binding sites” and “binding target.” In fact “Mxr1 transcriptional activator sequence” fails to
`
`appear in any scientific publication as determined using a search of Google Scholar. Therefore a
`
`
`
`13
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 14 of 27 PageID #: 14268
`
`POSITA would understand the phrase “Mxr1 transcriptional activator sequence” to mean the
`
`sequence coding for the Mxr1 transcriptional activator.
`
`
`
`27.
`
`Alper Reply paragraph 10 because addressed my interpretation of ’492 patent claim
`
`14 as referring to an embodiment in which more than one Mxr1 transcriptional activator is encoded
`
`by the nucleic acid molecule. Dr. Alper is incorrect that my interpretation would render two
`
`limitations in claim 14 duplicative. Dr. Alper does not appreciate the fact that claim 14 recites two
`
`different Mxr1 transcriptional activator sequences—one from P. pastor and one not limited to a
`
`species of origin, which may not be from P. pastoris. Those are Mxr1 transcriptional activators
`
`of different scope, they are not duplicative. I disagree with the remainder of Alper Reply 10 for
`
`reasons stated above.
`
`(b)
`
`A POSITA Would Understand “Mxr1” to Refer to a Native
`Transcriptional Activator, not a Non-Natural Variant
`
`28.
`
`As I noted in my Responsive Declaration at paragraphs 70, 124-26, the patents’
`
`specifications consistently refer to native Mxr1 as “Mxr1” and distinguish it from variant Mxr1,
`
`
`
`14
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 15 of 27 PageID #: 14269
`
`which the patents refer to as “variant Mxr1.” E.g., Ex. B12, ’656 patent, 27:5-32; Ex. 23 (SEQ ID
`
`NO:1). That is consistent with a POSITA’s understanding that Mxr1 is a naturally occurring
`
`transcriptional activator native to Pichia, but variants are human-made proteins that are not
`
`“Mxr1”; rather they may have different sequences, functionality, activity, structure, or other
`
`characteristics that make them different than Mxr1.
`
`29.
`
`I disagree with Alper Reply paragraphs 12-14. I do not dispute that Mxr1 native to
`
`one Pichia species can be recombinantly produced in Pichia of another species. But that misses
`
`the point. Dr. Alper does not dispute that a human-made variant Mxr1 is not "native” to Pichia of
`
`any species. Dr. Alper is confusing the issue of species to which Mxr1 is native—which the ’656
`
`patent claims specify as “from P. pastoris”—with the fact that native proteins are not human-made
`
`variants. A POSITA would understand that human-made variant Mxr1 proteins are not native to
`
`any Pichia species.
`
`30.
`
`In Alper Reply paragraph 15, Dr. Alper misguidedly points to Example 15 of the
`
`’656 patent to argue a construct including the native Mxr1 sequence with “6 additional amino acids
`
`introduced at the N-terminus” is engineered but still Mxr1. However, Dr. Alper does not
`
`appreciate that Mxr1 in that construct retains its full and native sequence, as the construct was
`
`made to include “[t]he open reading frame encoding the Mxr1 protein … from genomic DNA
`
`isolated from Pichia pastoris….” ’656 patent at 25:15-23. The construct did not vary the Mxr1
`
`transcriptional activator—it remained the native sequence as coded in the open reading frame. 6
`
`amino acids were introduced to the N-terminus during cloning, but the patent states it did not vary
`
`the native properties of the transcriptional activator, as “Pichia production strains containing the
`
`Mxr1 sequence having the additional 6 amino acids at the N-terminus and Pichia strains containing
`
`
`
`15
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 16 of 27 PageID #: 14270
`
`the wild type Mxr1 (i.e., without the additional 6 amino acids at the N-terminus) were
`
`indistinguishable in fermentation tanks.” Id. at 26:7-11.
`
`31.
`
`For the reasons in my Responsive Declaration and those set forth here, a POSITA,
`
`based on common understanding in the art and the disclosure of the ’492 and ’656 patents, would
`
`interpret the Mxr1 transcriptional activator terms, in the context of the claims, as construed by
`
`Motif. I disagree with Dr. Alper’s opinions to the contrary.
`
`C.
`
`Supplemental Opinions Regarding “Promoter Element”
`
`(a) My Approach to Claim Construction Is Correct
`
`32.
`
`Dr. Alper insinuates that my approach to claim construction in my Declaration is
`
`legally incorrect. Alper Rep. ¶¶18-20. I disagree. As I explained in my Declaration, I understand
`
`from counsel that intrinsic evidence is the most important source for determining the meaning of
`
`claim terms, but that extrinsic evidence—which I am informed includes expert testimony such as
`
`my Declaration—may also be useful. Decl. ¶34.
`
`33.
`
`In my Declaration, I reviewed the Expression System Patents’ intrinsic record and
`
`provided reasons why (1) Dr. Alper misinterprets the specifications, resulting in an incorrect
`
`definition of “promoter element” (Decl. §§VII, XI.B) and (2) a POSITA would not be reasonably
`
`certain of “promoter element” in view of the intrinsic record. Id. §XI.A. I did not “prioritize”
`
`extrinsic evidence. Rather, the intrinsic record does not explain or define what a “promoter
`
`element” is (as opposed to other concepts, such as “operably linked” or “expression element”).
`
`The question, therefore, is whether a POSITA would be reasonably certain of “promoter element’s
`
`scope” despite the patents’ lack of definition.
`
`34.
`
`The answer to this question is no, as I explained in my Declaration. In support, I
`
`discussed specific examples from technical literature which I believe will aid the Court in
`
`understanding the complexity of this term as well as illustrate a POSITA’s confusion over whether
`
`
`
`16
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 17 of 27 PageID #: 14271
`
`an expression system (either deliberately through design or by accidental inclusion) contains the
`
`claimed “promoter element.” Decl. §§XI.A.4-11.
`
`35.
`
`I note Dr. Alper states that “the intrinsic evidence provides the context or
`
`‘reference’” to establish the scope of “promoter element.” Alper Rep. ¶21. Dr. Alper evidently
`
`misunderstands my contrary position, which is that a “promoter element” only has meaning within
`
`the context of a known promoter (several are listed in the patents and available on GenBank), and
`
`that “promoter element” or “element” terminology is used subjectively throughout the technical
`
`literature. Decl. ¶135, §XI.A.8 (different approaches). Neither the intrinsic nor extrinsic evidence
`
`clarifies the metes and bounds of “promoter element” separate and apart from the known promoter,
`
`as I explained. Id. ¶135, 140, 163 & n.5, 176-77; §§XI.A.7 (TATA box location in context),
`
`XI.A.9 (minor changes affect expression), XI.A.10 (regulation depends on promoter localization).
`
`Dr. Alper’s understanding of “promoter element” is also fatally flawed by his misinterpretation of
`
`the intrinsic record, as explained below.
`
`(b)
`
`Dr. Alper’s Circular Analysis of the Intrinsic Record Confirms
`the Indefiniteness of “Promoter Element”
`
`36.
`
`Dr. Alper defines “promoter element” in terms of its supposed function (regulating
`
`transcription). Alper Rep. ¶17. Dr. Alper borrows this meaning from two different terms—
`
`“expression element” and “operably linked,” as I previously noted. Decl. ¶¶181-85. I explained
`
`the problems with Dr. Alper’s definition (Decl. §XI.B), but he does not meaningfully address my
`
`explanation in his Reply.
`
`37.
`
`Instead, Dr. Alper disagrees with my opinion that “elements” require localization
`
`for function by arguing that the claims and specification “provides such localization and
`
`specificity.” Alper Rep. ¶22. His Reply argument is premised on three teachings: (1) the claims’
`
`recitation of “methylotrophic yeast cell” and Mxr1, (2) the definition of the different term
`
`
`
`17
`
`

`

`Case 1:22-cv-00311-WCB Document 149 Filed 07/14/23 Page 18 of 27 PageID #: 14272
`
`“operably linked” (656 patent, 4:47-51) although he does not acknowledge this explicitly, and (3),
`
`a Mxr1 binding site. Alper Rep. ¶22. As in my Declaration, I disag