Chinese Patent No, 99805836.X
`Judgment
`
`Your Ref; Pi241R1 CN
`OurRef: LRL80822
`
`Beijing No. 1 Intermediate Court
`
`Administrative Judgment
`(2009) No. | Intermediate Court — Administrative Appeal - 661
`
`Plaintiff
`
`Genentech, Inc
`
`legal representative
`
`Atulya R. Agarwal
`
`1 DNA Way,
`Address:
`South San Francisco,
`CA, USS.A.
`
`chief
`vice
`director
`
`attorney,
`
`authorized representative Xingin Feng
`
`Dan Min
`
`an attorney from Liu,
`Shen & Associates
`a patent agent
`from
`Liu,
`Shen
`&
`Associates
`Patent Address: Yingu Plaza, |
`the
`Reexamination Board of 9 North 4th Ring West
`the National
`Patent Road, Haidian District,
`Office of China
`Beijing, P.R.C.
`
`Defendant
`
`Maoyu Zhang
`legal representative
`authorized representative Yi Feng
`
`Xinlei Yu
`
`Third Party
`
`Caihui Lee
`
`authorized representative Renmin Huang
`
`Summary
`
`vice director
`| an examiner from the
`Patent Reexamination
`
`Board of the National
`
`Patent Office of China
`
`an examiner from the
`Patent Reexamination
`
`Board of the National
`
`Patent Office of China
`
`room
`address:
`338 Xietu
`201-202,
`East Road, Huangpu
`District,
`Shanghai,
`PRC,
`
`from.
`a patent agent
`Lecome
`Intellectural
`- Property Agent Ltd.
`
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`Chinese Patent No, 99805836.x
`Judgment
`
`Your Ref: P124iR1.CN
`Our Ref: LRL80822
`
`Theplaintiff (Genentech, Inc.) was notsatisfied with the administrative decision on the
`patent issued by the Patent Reexamination Board of the National Patent Office of
`China and instituted this administrative procedure before the present court. The
`presentcourt accepted this case, and a panel was set up. Additionally, Caihui Lee was
`informedto participate in the case as the third party. A public court hearing was held
`on December 3, 2009. The agents ofthe plaintiff (Xingin Feng and Dan Min), the
`agents of the defendant (Yi Feng and Xinlei Yu), and the third party (Caihui Lee) and
`her agent (Renmin Huang)tookpart in the litigation. Now, the present caseis closed.
`
`History of the Case
`
`The defendantissued the Decision of Examination of the Request for Invalidation No.
`12385 (hereinafter referred to as “the sued decision”) on October 21, 2009, declaring
`the patent No. 99805836.X (hereinafter referred to as “the present patent”) completely
`invalid.
`
`The defendant submitted the copies of the following items to the court before the due
`date: 1. a copy of the PCT international application publication No. WO 97/04801 Al,
`totally 46 pages (i.e., Evidence D1 in the sued decision); 2. a copy of the specification
`of the present patent,
`to prove that the sued decision was made based on facts
`recognized properly, according to proper laws and through proper procedure,
`
`the sued decision was made based on facts recognized
`The plaintiff argued that,
`improperly.
`1, The technical problem to be solved of the present patentis different
`from that of D1, D1 is not the prior art similar to the present patent, and thus those
`skilled in the art can not conceive of seeking the technical solution of the composition
`of the present patent from D1.
`2, D1 neither discloses the composition of Claim 1 of
`the present patent, nor discloses the technical feature “the amount of the acidic
`variant(s) is less than 25%”. Thereis no data in Figures 5-8 or elsewhere in D1 which
`clearly identifies the presence of an acidic variant of anti-HER2 in the result of the
`cation exchange chromatography; nor docs D1 disclose less than 25% acidic variants
`or even any particular amountofanacidic variant.
`3. Even in the light of D1, those
`skilled in the art can not obtain the composition of the present patent based on the
`disclosure of D1, without undue experiments. D1 does not teach how to purify an
`anti-HER2 antibody orhowto identify or determine the presence ofthe acidic variants.
`D1 neitherrealizes the difficulty and problem encountered in purifying an anti-HER2
`antibody with cation exchange chromatography, nor indicates the need of removingthe
`acidic variants from a composition comprising an anti-HER2 antibody and one or more
`acidic variants thereof. Those skilled in the art can not obtain the composition of the
`present patentin light of the information provided in D1. The defendant understood
`and explained D1 in the way of ex post facto analysis.
`Indeed, it is not obviousto
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`Chinese Patent No, 99805836.X
`Judgment
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`YourRef: P1241R1 CN
`OurRef: LRL80822
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`those skilled in the art how to purify an anti-HER2 antibody composition to obtain the
`composition of Claim 1 of the present patent wherein the amountofthe acidic variants
`is less than 25%. Taken together, the plaintiff holds that the sued decision was made
`based on facts recognized improperly and lacked major evidence. The plaintiff
`requests for the court to revoke the sued decision.
`.
`
`To prove their statement,the plaintiff submitted a copy of the following evidenceto the
`court before the due date: 1. Evidence D1 in the sued decision; 2. the specification of
`the present patent; 3. Jiacheng Hua, et al., “Practical Chemical Technology on
`Proteins’, Shanghai Scientific & Technical Publishers, cover page, pages 1-3, 15 and
`16,all together 6 pages(i.e., the Counter-evidence 1 in the sued decision); and 4. Li’an
`Guo, “Theory and Technology on Purification of Proteins by HPLC”, ShanxiScientific
`& Technical Publishers, cover page, pages 1, 2, 4, 78, 79 and 387-394,all together 12
`pages
`(i.e., the Counter-evidence 2 in the sued decision).
`
`The defendantstated that they insisted on the opinion in the sueddecision on the
`inventiveness of the present patent, that the sued decision was made based on facts
`‘recognized properly, according to proper laws and through proper procedure, and that
`the request of the plaintiff did not have the basis of facts and laws, and requested the
`court to reject the request of the plaintiff and affirm the sued decision.
`
`The third party contested that she agreed with the defendant and that the statement of
`the plaintiff did not have the basis of facts and laws, and requested the court to affirm
`the sued decision and reject the request of the plaintiff.
`
`The third party did not submit any evidence to the court before the due date.
`
`After investigation, the plaintiff did not object the relevance, legality and authenticity
`of the evidences submitted by the defendant, but also did not agree on theirevidential
`function. The third party did not object the relevance,
`legality, authenticity and
`evidential function of the evidences submitted by the defendant. The defendant and
`the third party did not object the relevance, legality and authenticity of the evidences
`submitted by the plaintiff, but also did not agree on their evidential function.
`
`After examination, the court holdsthat, all evidences submitted by theplaintiff and the .
`defendantare related with the legality examination of the sued decision of the present
`case, and comply with the formal requirement for legality and authenticity, and
`therefore are acceptable.
`
`According to the valid evidence and the consistent statementof all parties concerned,
`the following facts are recognized by the court.
`
`The present case relates to a patent entitled “PROTEIN PURIFICATION BY ION
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`Chinese Patent No. 99805836.X
`Judgment
`
`Your Ref: P1241R1 CN
`OurRef: LRL80822
`
`EXCHANGE CHROMATOGRAPHY” issued on June 21, 2006 (hereinafter referred
`to as “the present patent”). or the present patent,
`the application number is
`99805836.X,the filing date is May3, 1999, and the priority date is May 6, 1998. The
`plaintiff is the patentee, GENENTECH INC. The granted claimsare as follows:
`
`1. Acomposition comprising a mixture of anti-HER2 antibody and one or moreacidic
`
`variants thereof, wherein the amountofthe acidic variant(s) is less than 25%.
`
`2. The composition of claim 1 further comprising a pharmaceutically acceptable
`
`carrier.
`
`3. The composition of claim 1 wherein the anti-HER2 antibody is humMAb4D5-8.
`
`The third party submitted a Request for Invalidation against the present patent on
`March 25, 2008 to the defendant, together with the following evidences.
`
`D1. WO97/04801 A1, a PCTinternational application published on February 13, 1997,
`46 pagesin total;
`|
`
`D2. W096/33208 Al, a PCTinternational application published on October 24, 1996,
`39 pagesin total;
`
`D3. Fusheng Han, “Chromatofocusing - a novel method for isolating protein”,
`Physiological Science, 1982; 2(9):13-14;
`
`the
`Isoelectrofocusing,
`“Immobilized pH Gradient
`D4. Raojun Guo et al,
`electrophoresis technique with the highest resolution nowadays, 1994, 21(2):143-146.
`
`Meanwhile, the third party submitted the Chinese translation of D1 (totally 47 pages)
`(i.e. a copy of granted Chinese patent No. 96195830.8, which was announced on June
`2, 2004), and some parts of D2 (totally 4 pages).
`”
`
`the third party stated that, (1) D1 discloses a
`In the Request for Invalidation,
`formulation comprising the anti-HER2 antibody composition of Claim | of the present
`patent (see Example 1 on Pages 18-27 of the English description of D1). Said protein
`which is formulated is preferably essentially pure (i.e. a composition comprising at
`least about 90%, 95% and 99% by weight of the protein) and desirably essentially
`homogeneous(i.e. free from contaminating proteins etc) (see Lines 5-9, Page 7 of the
`English description of D1).
`In the liquid state, rhuMAb HER2 was observed to
`degrade by deamination (30Asnof light chain) and isoaspartate formation via a cyclic
`imide intermediate, succinimide (102Asp of heavy chain)...
`slightly greater
`deamination was observed in the liquid protein formulation (see lines 13-15, page 19
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`Chinese Patent No. 99805836.X
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`YourRef: P1241R1 CN
`Our Ref: LRL80822
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`of the English description of Dl). Therefore, the formulation disclosed in D1 is a
`composition comprising a mixture of anti-HER2 antibody and one or more acidic
`variants thereof. Moreover,
`the condition of cation exchange chromatography on
`rhuMAb HER2 deamination and succinimide formation in D1 (see Pages 25-26 of the
`English description of D1)
`is identical with the chromatographic condition for
`determining rhuMAb HER2 inthe present patent. Meanwhile, Figures 5-8 in Dl
`disclose the result of the assays (see lines 20-38, page 4 of the English description of
`D1).
`Itis seen from the figures that the contentof protein not degraded was gradually
`decreased from 82% along with the storage of the rhnuMAb HER2 formulation, butthe
`content of the native protein remained no less than 75%.
`In other words, the content
`of degraded proteins in the formulation is less than 25%. The aforesaid disclosure
`suggests that, the amountofthe acidic variant(s) in the composition as disclosed in D1
`is less than 25%. Therefore, all the technical features of Claim | of the present patent
`are disclosed by D1, and Claim 1 lacks novelty as required by Article 22, paragraph 2
`of the Chinese Patent Law. The additional technical features of dependent claims 2-3
`are disclosed by D1, and Claims 2-3 lack novelty either.
`(2) Claims 1-3 do not
`possess inventiveness over D2 in combination with D3 or D4. D2 discloses an
`anti-HER2 antibody and the method for the purification of antibody proteins, D3 and
`D4 respectively disclose the methods of chromatofocusing or isoelectric focusing
`electrophoresis forthe purification of proteins. Using the methods disclosed by D2 or
`D3 or D4,it is possible to isolate the acidic variants in the antibody, so as to obtain the
`antibody composition of Claim 1. Therefore, Claim 1 does not comply with Article
`22, paragraph 3 of the Chinese Patent Law. The additional technical features of
`dependent claims 2-3 are disclosed by D2, and Claims 2-3 lack inventivenesseither.
`
`the defendant accepted said request, and issued the
`After a formality examination,
`Notification of Acceptance of the Request for Invalidationto the plaintiff and the third
`party on April 11, 2008, and transferred a copy of the Request for Invalidation andthe
`attachments thereof to the plaintiff, requiring the plaintiff to respond within the
`specified time limit.
`
`Thethird party
`On April 25, 2008, the third party submitted supplementary reasons.
`contested that, (1) Claims 1-3 are not inventive over Dl. DI discloses that in the
`liquid state, rhuMAb HER2 wasobserved to degrade by deamination (30Asn of light
`chain) and isoaspartate formation through a cyclic imide intermediate, succinimide
`(102Asp of heavy chain)... slightly greater deamination was observed in the liquid
`protein formulation. Meanwhile, those skilled in the art understandthat: the cation
`exchange chromatography in D1 can isolate the native protein from the degraded
`proteins,if a single elution peak from the cation exchange chromatographyis collected,
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`Chinese Patent No. 99805836,.X
`Judgment
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`Your Ref: P1241R1 CN
`OurRef: LRL80822
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`the native protein of a very high purity (more than 25%) will definitely be obtained.
`Therefore, those skilled in the art can obtain the technical solution of Claim 1 of the
`present patent withoutcreative work on the basis of D1 in view of common knowledge,
`and Claim 1 is not inventive. The additional technical features of dependent claims
`2-3 are disclosed by D1, and Claims 2-3 lack inventiveness either.
`(2) Claims 1-3 are
`not inventive over the combination of DI and D2. D2 discloses the method for
`preparation and purification of a rhuMab 4D5-8 HER2 antibody. The technical
`solutions of Claims 1-3 are obvious in light of D2 in combination with DI. @)
`Claims 1-3 are not inventive over D1 and D2 in combination with D3 or D4. D3 and
`D4 respectively disclose the methods of chromatofocusing or isoelectric focusing
`electrophoresis for the purification of proteins. Those skilled in the art can easily
`obtain the technical solutions of Claims 1-3 by applying the technical meansof D3 or
`D4 on the basis of D2 in combination with DI,
`
`In response to the Request for Invalidation submitted by the third part on March 25,
`2008, the plaintiff submitted observations on May 26, 2008.
`Theplaintiff stated that,
`(1) DI neither describes a compositionofthe presentpatent, nordiscloses the technical
`feature of “amount of the acidic variant(s) is less than about 25%”, nor provides a
`description of how to make such a composition. Hence, Claims 1-3 of the present
`patent are novel over D1.
`(2) D2 merely provides a method to remove an antibody
`fragment failing to correctly associate through disulfide bonding, which is different
`from the technical problem of decreasing the amount of the acidic variant(s) in the
`composition to be solved in the present patent. D3 and D4 do not disclose that said
`method can reduce the content of the acidic variants in the composition. Thus, said
`antibody composition of Claim | in the requested patent is inventive over D2, or
`D2+D3 or D2+D4.
`In addition,the plaintiff questions the authenticity of D3 and D4.
`
`_
`
`transferred a copy of the supplementary Observations and the
`The Defendant
`attachments submitted by the third party on April 25, 2008 to the plaintiff on June 20,
`2008. On July 21, 2008, the defendantissued the Notification of Oral Hearings of the
`Request for Invalidation to the twoparties, informing that an oral hearing with regard
`to the Request for Invalidation of the present patent would be held on August 27, 2008.
`Additionally, the defendant transferred a copy of the observation submitted by the
`plaintiff on May 26, 2008to thethird party.
`
`In response to the Supplementary Observations submitted by the requestor on April 25,
`2008, the plaintiff submitted Observations on August 5, 2008. The plaintiff made the
`following contentions,
`(1) The condition of cation exchange chromatography in D1
`is totally different from the condition for separating and collecting a composition
`comprising less than 25% acidic variants in the present patent. Thatis to say, it is not
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`Chinese Patent No. 99805836.X
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`Your Ref; P1241R1 CN
`OurRef; LRL80822
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`possible to obtain an anti-HER2 antibody composition comprising less than 25%
`acidic variants of Claim 1 of the present patent, using the cation exchange
`chromatography in D1, simply by collecting the single elution peak of the cation
`exchange chromatography.
`(2) On page 19, lines 25-27, D1 explains that the “major
`degradation route for
`this protein [rhuMAb HER2] upon lyophilization was
`aggregation, and therefore the protein stability was assessed by non-denaturing size
`exclusion chromatography to measure the recovery of intact native protein.” D1
`emphasizes a non-degraded protein that
`is non-aggregated protein rather than a
`composition without acidic variants.
`(3) The Figures 5-8 of D1 neither identifies
`whetherthe percentage protein otherthan native protein represents acidic variants or
`not, nor teaches how to reduce the amountof acidic variants to less than 25% by
`specific chromatographic condition of cation exchange chromatography. Therefore,
`from the disclosure of D1, those skilled in the art are not motivated to obtain the
`composition of the present patent and the method to make the composition. Claims
`1-3 are inventive over D1.
`In addition, the technical solutions of Claims 1-3 in the
`presentpatentare inventive over D1 in view of D2, or over D1 in view of D2 and D3,
`or over D1 in view of D2 and D4.
`
`The Defendant transferred the copies of the response submitted by the plaintiff on
`August 5, 2008 to the third party on August 19, 2008.
`
`On August 27, 2008, the oral hearing was held as scheduled. The third party and the
`plaintiff and their respective agents were present in the oral hearing. The defendant
`investigated the reasons and relevant facts for invalidation with regard to the present
`case one by one. The parties concerned sufficiently stated their respective opinions.
`The facts determined by the investigation in the oral hearing were listed as follows.(1)
`The two parties did not object the identity and qualification ofthe staff of the opposing
`party, and did not request evasion of any member in the Panel,
`(2) Thethird party
`gave up D2 and the reasonthat Claims1-3 are not inventive over D2 in the oral hearing.
`(3) The third party clarified the grounds and scope for invalidation in the oral hearing
`as follows: Claims 1-3 of the present patent are not novel over D1; Claims1-3 of the
`present patent are not inventive over D1 alone or D1 in combination with D3 or D4.
`(4) The third party presented the copies of D3 and D4 stamped with the seal of
`information service department, Shanghai Technology and Science Intelligence
`Research Institutes, Shanghai Library. The plaintiff did not object the authenticity,
`legality, relevance and public availability of D3 and D4 submitted by the third party.
`(5) The plaintiff did not object
`the authenticity,
`legality, relevance and public
`availability of D1 and the accuracy of the translations thereof.
`(6) The plaintiff
`submitted Counter-evidence 1 and Counter-evidence 2 and the copies thereof as
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`Chinese Patent No, 99805836.X
`Judgment
`
`Your Ref: P1241R1 CN
`Our Ref: LRL80822
`
`common knowledge evidence during the oral hearing. The third party did not object
`to the authenticity, legality, relevance and public availability of Counter-evidence |
`and Counter-evidence 2.
`
`The counter-evidences submitted by the plaintiff during the oral hearing were as
`following.
`
`Jiacheng Hua, et al., “Practical Chemical Technology on
`Counter-evidence 1:
`Proteins”, Shanghai Scientific & Technical Publishers, cover page, pages 1-3, 15 and
`16, all together 6 pages of the copies.
`
`Counter-evidence 2; Li’an Guo, “Theory and Technology on Purification of Proteins
`by HPLC”, Shanxi Scientific & Technical Publishers, cover page, pages 1, 2, 4, 78, 79
`and 387-394, all together 12 pages.
`
`Theplaintiff and the third party respectively submitted the statements presented at the
`oral hearing on September| and September3, 2008.
`
`Based on the above procedure, the defendant takes the position that,
`
`1. With regard to the text of the present patent
`
`The sued decision is based on the text of the present patent that was granted and
`announced,
`
`2. With regard to the grounds and evidenceforthe invalidation
`
`The third party gave up D2 and the relevantreasons during the oral hearing. Thus,the
`defendant did not consider this evidence and the relevant reasons, D1 is a patent, and
`D3 and D4are published journals. The third party presented the copies of D3 and D4
`stamped with the seal of information service department, Shanghai Technology and
`Science Intelligence Research Institutes, Shanghai Library. The plaintiff did not
`object the authenticity, legality, relevance and public availability of D1, D3 and D4 and
`the accuracy of the translation of D1 submitted by the third party, All these three
`evidences were published before the date offiling of the present patent. Hence, Dl,
`D3 and D4 can be regarded as the prior art
`to comment on the novelty and
`inventiveness of the present patent. The third party did not object the authenticity,
`legality, relevance and public availability of Counter-evidence 1 and Counter-evidence
`2 submitted by the plaintiff as common knowledge. Thus, the defendant accepted
`Counter-evidence| and Counter-evidence2.
`
`Based on the statements during the oral hearing of the third party, grounds for the
`invalidation were that: Claims 1-3 are not novel over D1 and do not comply with the
`provision of Article 22, paragraph 2 of the Chinese Patent Law, Claims 1-3 are not
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`Chinese Patent No, 99805836,X
`Judgment
`
`Your Ref: P1241R1 CN
`OurRef: LRL80822
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`inventive over D1 alone or in combination with D3 or D4, and do not comply with the
`provision of Article 22, paragraph 3 of the Chinese Patent Law.
`
`3, With regard to Article 22, paragraph 3 of the Chinese Patent Law
`
`According to Article 22, paragraph 3 of the Chinese Patent Law, inventiveness means
`that, as compared with the technology existed before thefiling date, the invention has
`prominentsubstantive features and represents a notable progress and that the utility
`model has substantive features and represents progress.
`
`the claimed technical
`For determining whether an invention is inventive or not,
`solution shall be compared with the closest prior art so as
`to determine the
`distinguishing features of the claimed invention.
`If the technical solution with the
`distinguishing features can be figured out by those skilled in the art through logical
`analysis or reasonable inference based onthe closestpriorart, said technical solutionis
`obvious and does not possess inventiveness.
`
`Claim | of the present patent is directed to a composition comprising a mixture of
`anti-HER2 antibody and one or more acidic variants thereof, wherein the amountof the
`acidic variant(s) is less than 25%. D1 discloses a formulation comprising a HER2
`antibody composition, wherein the HER2 antibody protein is preferably essentially
`pure(i.e. a composition comprisingat least about 90%, 95% and 99% by weight of the
`protein) and desirably essentially homogeneous(i.c. free from contaminating proteins
`etc.) (see Lines 5-9, Page 7 of the English description of D1). Slightly greater
`deamination is observed in said HER2 antibody protein formulation. The rhuMAb
`HER? is observed to degrade in the aqueous solution by deamination (30Asnoflight —
`chain) or isoaspartate formation via a cyclic imide intermediate, succinimide (102Asp
`of heavy chain) (see lines 13-15, page 19, lines 14-16, pages 26 of the English
`description of D1). The amount ofnative protein in the rhuMAb HER2 formation
`upon deamination or succinimide formation is measured by cation exchange
`chromatography (see lines 13-20, page 26 of the English description of D1).
`Meanwhile, Figures 5-8 in D1 disclosethe result of the assays (see lines 20-38, page 4
`of the English description of D1).
`It is seen from the figures that the content of the
`non-degraded protein is gradually decreased from 82% along with the storage of the
`thuMAb HER2formulation, but the contentof the native protein remainednoless than
`75%.
`In other words, the content of degraded proteins in the formulation is less than
`25%.
`
`Therefore, D1 discloses a composition comprising an anti-HER2 antibody and
`degraded variants thereof with amount less than 25%. The technical solution of
`Claim 1 differs from the composition of D1 in that: D1 does notrecite the technical
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`feature that the amountof the acidic variant(s) is less than 25% in said composition.
`However, those skilled in the art can see from the disclosure of D1 that said cation
`exchange chromatography has measured the content percentage of the native protein
`and the degraded protein. The content of the degraded protein is in a range of
`18%-25% (the corresponding time point is in a range of 0-15 days). Since the major
`degradation route for HER2 antibody is deamination, the acidic variants of anti-HER2
`antibody in the present patent mean that a variant of the HER2 antibody polypeptide
`formed by deamination or deamidation is more acidic than the initial polypeptide (see
`lines 19-33, page 5 of the description of requested patent)..Thus, said acidic variants
`are degraded protein. Thereby,
`it can be deduced that the amount of the acidic
`variant(s) in the composition formulation of a HER2 antibody protein measured in D1
`is definitely less than 25%. Thus, based on the anti-HER2 antibody composition
`disclosed in D1, those skilled in the art can determine that the amountof the acidic
`variants in the HER2 antibody protein composition disclosed in D1 is less than 25%
`through logical analysis and reasonable deduction. Therefore, the technical solution
`of Claim | of the present patent is obvious to those skilled in the art, and does not
`possess inventiveness over D1.
`
`Theplaintiff admitted in the oral hearing that D1 discloses a composition comprising a
`mixture of anti-HER2 antibody and one or more acidic variants thereof, butstill
`alleged that: 1) The result of the assays disclosed by Figures 5-8 in D1 can not prove
`that
`the value 18% in the composition means acidic variants, or the value 82%
`indicates the native protein in which all the acidic variants have been ‘separated and
`removed.
`It
`is predictable that said native protein contains unpurified and
`unseparated acidic variants. The Figures 5-8 of D1 neither determines whether the
`percentage of the protein other than the native protein represents the acidic variant, nor
`teaches how to reduce the amount of acidic variants to less than 25% by the specific
`chromatographic condition of cation exchange chromatography.
`2) The condition of
`cation exchange chromatography in D1 is different from the condition for separating
`and collecting a composition comprising less than 25% acidic variants in the present
`patent. Thatis to say, it is not possible to obtain an anti-HER2 antibody composition
`comprising less than 25% acidic variants of Claim | of the present patent, using the
`cation exchange chromatographyin D1, simply by collecting the single elution peak of
`the cation exchange chromatography.
`3) On page 19, lines 25-27, D1 explains that
`the “major degradation route for this protein [rhuMAb HER2] upon lyophilization was
`aggregation, and therefore the protein stability was assessed by non-denaturing size
`exclusion chromatography to measure the recovery of intact native protein.” D1
`emphasizes a non-degraded protein that is not the aggregated protein instead of a
`composition without acidic variants. Thus, the result of the assays disclosed in Dl
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`Pfizer Ex. 1028
`Page 10 of 15
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`

`Chinese Patent No. 99805836.X
`YourRef: P1241R1 CN
`Judgment
`OurRef: LRL80822
`mainly showsthe degradation of the protein caused by aggregation beforeorafter the
`reconstruction of formulation, which has no relation to the degradation of the acidic
`variants,
`In conclusion, D1 neither discloses the composition of the present patent,
`norteaches how to make the composition. From the disclosure of D1, those skilled in
`the art are not motivated to obtain the composition of the present patent and can not
`know how to make
`the composition. Meanwhile,
`the plaintiff
`submitted
`Counter-evidence 1 and Counter-evidence 2 to demonstrate that in general, there is
`difficulty of purification with respect of a protein.
`It is not possible to obtain a
`composition comprising a mixture of anti-HER2 antibody and acidic variants thereof,
`wherein the amount of the acidic variant(s) is less than 25% as defined by Claim 1 of
`the present patent, using the cation exchange chromatography in D1, simply by
`collecting the single elution peak of the cation exchange chromatography. Therefore,
`Claim | is inventive over D1.
`
`The defendant made the following contentions 1) According to the definition of “an
`acidic variant” recited on lines 19-33, page 5 of the description of the present patent,
`the acidic variant of anti-HER2 antibody means that a variant of a HER2 antibody
`polypeptide formed by deamination or deamidation is more acidic than the initial
`polypeptide. Such acidic variants are formed by degradative denaturation of the
`intact anti-HER2 antibody polypeptide.
`Thus, D1 discloses
`a composition
`comprising an anti-HER2 antibody and the acidic variants thereof, as the acidic
`variants formed by deamination and the like are present in the anti-HER2 antibody
`preparation disclosed in D1,
`2) It is seen from the brief description for Figures 5-8 of
`D1 and the description of measuring steps on rhuMAb HER2formulation in Example
`1 of D1 that the % native protein in Figures 5-8 is the non-degraded protein percentage,
`rather
`than the % native protein comprising degraded proteins, or comprising
`unpurified and un-separated acidic variants, as alleged by the plaintiff. Furthermore,
`the plaintiff failed to provide any evidence proving that said acidic variants are
`contained in the % native protein, instead of being contained in the 18% percentage.
`3) Those skilled in the art know that the cation exchange chromatography for the
`measurement and purification of a HER2 antibody composition certainly involves
`different conditions. Those skilled in the art can determine andadjust the selection of
`such conditions according to the conventional means. Merely based on the different
`chromatographic conditions, there is no reasonable ground to deny the fact that the
`amountofacidic variants in the composition measured in Figures 5-8 of D1 is less than
`25%.
`4) The Counter-evidence 1 and Counter-evidence 2 recite the possible
`problems to purify a protein by cation exchange chromatography, such as strength of .
`ions, the concentration of the buffers, the pH value and so on. However, the general
`description of the condition of the experiments neither implies the specific unsolved
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`Pfizer Ex. 1028
`Page 11 of 15
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`Pfizer Ex. 1028
`Page 11 of 15
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`

`

`Chinese Patent No, 99805836.X
`Judgment
`
`YourRef: P1241R1 CN
`OurRef: LRL80822
`
`technical problems during the purification of a specific HER2 antibody, nor directly or
`indirectly prove that
`the amount of the acidic variant(s)
`in a HER2 antibody
`composition measured in D1 can not be less than 25%.
`5) Moreover, Claim 1 does
`not define the composition by the process.
`In other words, Claim | is directed to a
`composition that can be prepared by any processes. The plaintiff failed to provide
`sufficient reasons and evidence in the responses and oral hearing to prove that the
`amountofthe acidic variant(s) in a HER2 antibody composition that is less than 25%
`can not be obtained underthe chromatographic condition disclosed by D1 or underthe
`conditions varied slightly. The plaintiff argued thatsinceit is ratherdifficult to purify
`an ordinary protein, the composition of Claim 1 can not be obtained by the meansin
`the prior art except for the process in the requested patent. Said argument is nota7
`convincing.
`
`The dependentclaims 2 and 3 define that the composition of Claim | further comprises
`a pharmaceutically acceptable carrier and that
`the anti-HER2 antibody in said
`composition is himMAb4D5-8, respectively. All above additional technical features
`are disclosed by D1 (see pages 14-15, line 2 of page 19 of the English description of
`D1), Thus, Claims 2-3 do not possess inventiveness as required by Article 22,
`paragraph 3 of the Chinese Patent Law overD1, either.
`
`To sum up, since D1 is sufficient enough to prove that Claims 1-3 do not possess
`inventiveness a